Drug development

12 Key excerpts on "Drug development"

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  eBook - ePub

  Pharmaceutical Biotechnology

  Concepts and Applications

  • Gary Walsh(Author)
  • 2013(Publication Date)
  • Wiley

    (Publisher)

  4

  The Drug development process

  4.1 Introduction

  In this chapter, the life history of a successful drug will be outlined (summarized in Figure 4.1 ).

  A number of different strategies are adopted by the pharmaceutical industry in their efforts to identify new drug products. These approaches range from random screening of a wide range of biological materials to knowledge-based drug identification. Once a potential new drug has been identified, it is then subjected to a range of tests (both in vitro and in animals) in order to characterize it in terms of its likely safety and effectiveness in treating its target disease. The developer will also undertake manufacturing-related development work (development and initial optimization of upstream and downstream processing; Chapters 5 and 6), as well as investigating suitable potential routes of product administration.

  After completing such preclinical trials, the developing company apply to the appropriate government-appointed agency, e.g. the Food and Drug Administration (FDA) in the USA, for approval to commence clinical trials (i.e. to test the drug in humans). Clinical trials are required to prove that the drug is safe and effective when administered to human patients, and these trials may take 5 years or more to complete. Once the drug has been characterized, and perhaps early clinical work is underway, the drug is normally patented by the developing company in order to ensure that it receives maximal commercial benefit from the discovery.

  Upon completion of clinical trials, the developing company collates all the preclinical and clinical data they have generated, as well as additional pertinent information, e.g. details of the exact production process used to make the drug. They submit this information as a dossier (a multi-volume work) to the regulatory authorities. Regulatory scientific officers then access the information provided and decide (largely on criteria of drug safety and efficacy) whether the drug should be approved for general medical use.

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  Available until 9 Feb |Learn more

  Pharmaceutical Dosage Forms and Drug Delivery

  Revised and Expanded

  • Ram I. Mahato, Ajit S. Narang(Authors)
  • 2017(Publication Date)
  • CRC Press

    (Publisher)

  Chapter 2

  Drug development

  LEARNING OBJECTIVES

  On completion of this chapter, the students should be able to

  1. Describe the Drug development and regulatory process.
  2. Discuss the role of the Food and Drug Administration (FDA) in the approval of a dosage form.
  3. Differentiate between an investigational new drug (IND) application, a new drug application (NDA), and a biologics license application (BLA).
  4. Identify the three key components of pharmaceutical development.
  5. Identify the objectives and key deliverables of the three stages of clinical trials.
  6. Describe a drug’s life cycle and how it is driven by intellectual property rights.

  2.1 INTRODUCTION

  The process of discovery and development of safe and effective new medicines is long, difficult, and expensive. A new molecular entity (NME), sometimes also called a new chemical entity (NCE), is characterized for its potential therapeutic applications and toxicological profile in nonprimate species, which is followed by extensive animal and human testing. On average, it costs a company more than $1 billion and 10–15 years to get one drug from the laboratory to patients. Only five in ~5000 compounds that enter preclinical testing make it to human testing. Only one of those five drugs entering human clinical trials is approved for commercialization.

  New drugs include prescription drugs, over-the-counter (OTC) medications, generic drugs, biotechnology products, veterinary products, and/or medical devices. Over-the-counter drugs do not require a physician’s prescription. Drug development also focuses on new dosage forms, routes of administration, and delivery devices for existing drugs. A typical drug discovery process entails target identification, such as a protein or an enzyme whose inhibition may help in a disease state. The structural features necessary in a potential drug candidate are identified using in silico molecular modeling. Several drugs may be synthesized using combinatorial chemistry and screened for in vitro activity in high-throughput assays. The lead candidates are then synthesized in larger quantities, screened for biological activity, and further optimized to maximize the affinity, specificity, and potency. A highly specific compound that only binds the target site is likely to have minimal nontarget effects, which often lead to adverse effects and toxicity related to the mechanism of drug action. High affinity for the target site, often resulting in high potency (low dose for the desired pharmacological effect), minimizes the required dose of a compound, which can reduce adverse effects and toxicities not associated with the drug’s mechanism of action. Such a drug candidate is then identified as an NME (Figure 2.1

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  Monte Carlo Simulation for the Pharmaceutical Industry

  Concepts, Algorithms, and Case Studies

  • Mark Chang(Author)
  • 2010(Publication Date)
  • CRC Press

    (Publisher)

  Chapter 3 Overview of Drug development This chapter will cover the following topics: • Drug Discovery • Preclinical Development • Clinical Development 3.1 Introduction Pharmaceutical research and biotechnology companies are “devoted to in-venting medicines that allow patients to live longer, healthier, and more productive lives.” — “Who We Are,”PhRMA, www.phrma.org. A pharmaceutical or biopharmaceutical company is a commercial busi-ness licensed to research, develop, market, and/or distribute drugs, most commonly in the context of healthcare. They are subject to a variety of laws and regulations regarding the patenting, testing, and marketing of drugs, particularly prescription drugs. From its beginnings at the start of the 19th century, the pharmaceutical industry is now one of the most successful and influential, attracting both praise and controversy. Most of today’s major pharmaceutical companies were founded in the late 19th and early 20th centuries. Key discoveries of the 1920s and 1930s, such as insulin and peni-cillin, became mass-manufactured and distributed. Switzerland, Germany, and Italy had particularly strong industries, with the UK and US following suit. Attempts were made to increase regulation and to limit financial links between pharmaceutical companies and prescribing physicians, some by the relatively new US FDA. Such calls increased in the 1960s after the thalidomide tragedy came to light, in which the use of a new tranquilizer 81 82 Monte Carlo Simulation for the Pharmaceutical Industry in pregnant women caused severe birth defects. In 1964, the World Medical Association issued its Declaration of Helsinki, which set standards for clini-cal research and demanded that subjects give their informed consent before enrolling in an experiment. Pharmaceutical companies were then required to prove efficacy in clinical trials before marketing drugs. The industry remained relatively small until the 1970s when it began to expand at a greater rate.

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  Promising Pharmaceuticals

  • Purusotam Basnet(Author)
  • 2012(Publication Date)
  • IntechOpen

    (Publisher)

  After this stage, the molecule is said to have transformed from a molecule to drug. Even after the launch of the drug in the market, the post-marketing surveillance and pharmacovigilance program is being carried out to find out whether any new adverse reaction or incompatibilities towards other agents, when given as combination therapies. (Congreve, et al., 2005). Figure 1 depicts the entire drug discovery process with the tentative timeline. Fig. 1. Drug discovery and development process (Lombardino and Lowe, 2004). 2. Drug discovery process Drug discovery process basically is a patient oriented science, where researchers strive to improve the existing drugs or invent a totally new chemical entity, which should be ideally more potent than any existing drug of a similar category. If not, then at least it should be safer than those existing. This process is a very time consuming and expensive activity, calling for the expertise of many eminent researchers. It takes nearly 12-14 years of exhaustive research and a huge amount of financial investment for the discovery of a single drug. Right from the chemical synthesis to its clinical development and finally formulating it to a suitable form. Failure at any stage would mean a huge loss for the company. Hence, a lot of planning is required even before the project is underway. Recently, with the use of technology the process is becoming a less risky business, because of the ability of the computers to predict the possible outcomes. This will surely reduce the efforts in fruitless directions (Augen, 2002). Promising Pharmaceuticals 22 The following paragraphs shall discuss the various stages of drug discovery process. 2.1 Identification of biological targets The human body functions normally by the virtue of the biochemical process which go on, producing all the necessary chemicals required for numerous functions to undergo smoothly within the body.

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  Careers with the Pharmaceutical Industry

  • Peter D. Stonier(Author)
  • 2003(Publication Date)
  • Wiley

    (Publisher)

  Assuming that these later compounds possess the required activity pro¢le, further structural modi¢cation will then be undertaken to provide a drug candidate with the right pro¢le for exploratory development. Development The development process is inherently di¡erent in its aims and modus operandi from that of discovery research.The main objective of Drug development is to assess the therapeutic potential and obtain marketing approval for new chemical entities 32 BACKGROUND TO MEDICINES RESEARCH AND DEVELOPMENT with maximum speed, optimum cost and high quality of the package submitted to regulatory authorities. Key ingredients include: . Detailed planning with fast track to phase I studies in man; . Product pro¢les clearly de¢ned and agreed with marketing; . Strong input from regulatory a¡airs and medical marketing; . Project managers with good organisational, communication and analytical skills; . Project team members with good technical, problem-solving and communica-tion skills, coupled with follow-through ability; . Checkpoints, milestones and management systems to assess project progress; . E¡ective use of information technology; . Flexible use of resources to create and disband teams when required; . E¡ective links between process research and production to aid the early involve-ment of production. In addition to the need to plan and organise the development process there is also a clear need for innovation and creativity in the solving of de¢ned, but often techni-cally di⁄cult, problems associated with developing a new drug.Thus, although the need for an innovative climate is not as critical as in discovery, it is recognised that development scientists must be given the opportunity to stay at the forefront of their disciplines through the practice of state-of-the-art science and publication of research ¢ndings as well as via collaborative interaction with other scientists in R&D.

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  The Practice of Medicinal Chemistry

  • Camille Georges Wermuth(Author)
  • 2011(Publication Date)
  • Academic Press

    (Publisher)

  Development of New Drugs: Legal and Economic Aspects Bryan G. Reuben Section Editor Part VIII This page intentionally left blank 857 Copyright © 2008, Elsevier Ltd All rights reserved. Wermuth’s The Practice of Medicinal Chemistry Chapter 42 I. INTRODUCTION Drug-development companies need to improve efficiency to sustain growth and profitability. The rate of technical devel- opment must be high and consistent. Formulating and adapt- ing a future drug product as fresh information is provided by researchers in different disciplines is a continuous challenge. There is always something to improve. Because of this contin- uous iterative adaptation, formulation development can easily become the critical stage in the overall development process. This chapter presents information on the discovery and development processes. It draws attention to some strategic technical points that are important if a project is to progress rapidly and without repetition. It indicates hidden pitfalls. It aims to provide background information regarding for- mulation development to enable researchers to ask the right questions. Links are provided to the essential regulatory documents of the European Regulatory Agency, the FDA and the ICH organization. The development of a standard oral dosage form is taken as an example. II. DISCOVER THE DRUG SUBSTANCE Knowledge of the properties of a drug substance increases during the development process. Usually lead compounds are obtained from high-throughput screening, the literature or competitors’ compounds. Initial work focuses on potency and selectivity. Later, properties influencing drug disposi- tion become important and need to be optimized in parallel to potency. Finally, some substance characteristics critical for developability are determined in early development or at an interface between research and development. It has become common practice in early development phase to investigate a package of compounds as opposed to a single substance.

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  Essential CNS Drug Development

  • Amir Kalali, Sheldon Preskorn, Joseph Kwentus, Stephen M. Stahl(Authors)
  • 2012(Publication Date)
  • Cambridge University Press

    (Publisher)

  Additionally, Chapter 3: Essential CNS Drug development – pre-clinical development 47 proteins are optimized for maximum expression in cellular systems, maximum product quality, homogeneity, stability, and solubility. Further changes can be made to enhance biological stability and the inclusion of additional functional domains. More recently, in addition to protein-based biologics, biopharmaceuticals are extending to nucleic acid-based or other novel technologies such as RNA interference (RNAi) and aptamers. Translational neuroscience and pre-clinical development Translational research is defined as “the transfer of knowledge gained from basic research to new and improved methods of preventing, diagnosing, or treating disease, as well as the transfer of clinical insights into hypotheses that can be tested and validated in the basic research laboratory” (Hall, 2002). The goal is to provide a better understanding of the disease in question by linking basic and clinical research at every stage of the drug R&D value chain. Driven totally by data, it is a two-way iterative process where drug discovery and development is complemented by the pursuit of understanding human diseases. In forward translation, one will use pre-clinical findings to guide clinical studies and the development plan (e.g. disease indications, patient populations, dose selection, dosing regimen). In back-translation, one will use clinical data to improve pre-clinical drug discovery (e.g. identify and validate drug targets, understand disease mechanisms, develop predictive models/biomarkers). Animal models used in most drug discovery efforts do not mimic the human diseases in question. In no other therapeutic area is this more relevant than diseases of the CNS. Therefore significant risk is taken when compounds are brought to clinic trials without reassuring data that the mechanism in question has disease relevance.

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  Pharmacology

  Drug Actions and Reactions

  • Carol T. Walsh, Rochelle D. Schwartz-Bloom(Authors)
  • 2004(Publication Date)
  • CRC Press

    (Publisher)

  16 The Development and Evaluation of New Drugs Until the early part of the nineteenth century, the only drugs available were crude preparations of plant, animal or mineral origin. The modern era of pharmacology was ushered in with advances in chemistry and the development of fundamental and essential methods of physiologic experimentation. The former permitted the isolation, purification, and identification of active components of older preparations as well as the synthesis of new agents. And the development of experimental methods made it possible not only to distinguish worthless remedies from those that were useful, but also to determine how drugs produce their effects in the living organism. Once given the necessary tools and techniques, pharmacology grew at an accelerating pace, paralleling the rapid advances in related disciplines and spurred on by the extensive research and development within the pharmaceutical industry itself. The proliferation of new drugs, the increased number of diseases beneficially affected by drugs, and the progress in understanding basic mechanisms of drug action are the tangible effects of this evolution. This growth reached its peak in the decade following World War II with the almost explosive expansion of basic research in the biomedical sciences. The rate of development, at least of new drugs, then declined and leveled off, until advances in molecular biology spurred another growth phase in drug discovery. Advances are continually being made, and new agents are constantly being added to the therapeutic armamentarium. In this chapter we shall trace the development of a new drug from its genesis in the chemist’s laboratory to its final acceptance as a safe and useful therapeutic agent. DEVELOPMENT AND EVALUATION IN THE LABORATORY The First Step—Discovering a Drug Serendipity coupled with astute observations by alert investigators has played a role in the development of some very important drugs.

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  Job$ in the Drug Indu$try

  A Career Guide for Chemists

  • Richard J. Friary(Author)
  • 2000(Publication Date)
  • Academic Press

    (Publisher)

  From its practitioners, suc-cessful chemical development projects demand scrutiny of chemical reac-tions and knowledge of mechanistic organic chemistry. They need talent and experience to devise problem-solving experiments and to execute them. Chemical development efforts represent applied science; they are market driven, perhaps even more than their counterparts in discovery research. Discovery and Development of Drugs 63 Only those syntheses merit development that offer patentable novelty as chemical processes and that furnish an important product. At the outset of development, and at its conclusion, the structure and properties of the final product are already known. It possesses the desired therapeutic effect in an animal model of the human disease and the potential to serve an existing market. Development efforts are not devoted to improving the biological profile of a clinical candidate by finding a successor or a back-up drug. Finding a manufacturing synthesis. Chemical development projects have dual aims. First, if clinical trials succeed and the Food and Drug Administra-tion approves launching, then development chemists must be ready with a tested manufacturing process. To devise and demonstrate such a process can represent a formidable task, if tens or thousands of tons of drug are needed as the so-called bulk active ingredient. Because of its large scale, a good manufacturing process draws on the talents of organic chemists, chemical engineers, and pharmacoeconomists, to name only a few kinds of experts. Evaluating iiazards. When a drug begins chemical and clinical develop-ment, the final choice of a manufacturing synthesis may lie far ahead. Nev-ertheless, the initial demand for large amounts of an experimental drug raises safety concerns that are satisfied early in chemical development.

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  Drug Safety Evaluation

  • Shayne Cox Gad, Dexter W. Sullivan(Authors)
  • 2022(Publication Date)
  • Wiley

    (Publisher)

  The popular image of “magic bullets”—(a phrase first used by Ehrlich in 1905)— is the essence of today’s target-directed approaches to drug discovery. More recently, as this book will show, all new categories of therapeutic entities (biotechnology-derived monoclonal antibodies, cell tissue therapies, and gene therapies) have entered use in medicine as “drugs” (Table 1.6). THE Drug development PROCESS AND THE GLOBAL PHARMACEUTICAL MARKETPLACE 11 1.4 THE Drug development PROCESS While the processes for the discovery of new potential therapeutic drugs are very diverse (Gad, 2005; Choerghade, 2006; Mathieu, 2008; Gad, 2016), once the decision is made to move a candidate compound forward to (hopefully) market approval, the general process is well defined in the compo- nents of its regulatory requirements (though with significant variability and frequent change in its details). It has many components which are beyond the scope of safety assessment, and therefore of this volume (including chemical development, clinical evaluation, and a host of regulatory actions.) The process generally proceeds by way of getting regulatory concurrences for entering clinical trials, then pro- ceeding through three (not strictly defined) stages of clinical trials (Phase I, Phase II, and finally Phase III), followed by submission of a full set of documents, data, and a proposed label seeking regulatory approval for a marketing application. The metrics of this process as it now operates make can- cer the most prevalent therapeutic target for new drugs, with perhaps as many as one-third of all new drug candidates being in this claim area. Heart diseases, CNS diseases, ner- vous system diseases, and immune system disorders follow in order of current popularity (Table 1.4). According to the Center for Drug Evaluation and Research (CDER) 12 328 different new (NME) drugs and nonbiosimi- lar INDs are in development in 2019, spread across the entire course of the development process.

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  Drug Discovery and Development, Volume 1

  Drug Discovery

  • Mukund S. Chorghade(Author)
  • 2006(Publication Date)
  • Wiley-Interscience

    (Publisher)

  drug regulatory process. TABLE 2.2 Acronyms and Designations an eye toward enhancing the efficacy of substances thought to be of therapeutic value. 19 In the United States, medicinal chemistry became formalized as a graduate-level discipline about 75 years ago within the academic framework of pharmacy education. From this set- ting, overviews of medicinal chemistry’s subject matter have been offered to undergradu- ate pharmacy students for many years. 20,21 Understanding structure–activity relationships (SARs) at the level of inherent physical organic properties (i.e., lipophilic, electronic, and steric parameters) coupled with consideration of molecular conformation soon became the hallmark of medicinal chemistry research. Furthermore, it follows that because these fun- damental principles could be useful during the design of new drugs, applications toward drug design became the principal domain for a still young, basic science discipline. Per- haps somewhat prematurely, medicinal chemistry’s drug design role became especially im- portant within the private sector, where its practice quickly took root and grew rampantly across the rich fields being staked out within the acres of patents and intellectual property that were of particular interest to the industry. 2.2.2 Early Developments As a more comprehensive appreciation for the links between observed activity and pharma- cological mechanisms began to develop about 50 years ago and then also proceeded to grow rapidly in biochemical sophistication, medicinal chemistry, in turn, entered into what can now be considered to be an adolescent phase. Confidently instilled with a new understand- ing of what was happening at the biomolecular level, the ensuing period was characterized by the high hope of being able to design new drugs independently in a rational (i.e., ab initio) manner rather than by relying solely on nature’s templates and guidance for such.

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  Drug Discovery and Development, Volume 2

  Drug Development

  • Mukund S. Chorghade(Author)
  • 2007(Publication Date)
  • Wiley-Interscience

    (Publisher)

  This led to the devel- opment of arguably the most important piece of documentation in Drug development in the United States, the new drug application (NDA). If that document passes the FDA approval process, the drug is deemed safe and effective within the scope of the clinical program and may be given to patients. The content and format of the NDA will continue to evolve, but the basic tenets have endured: Ensure full comprehension of the participant as to the risks of the study and its methods of eliciting usable results, establish safety and efficacy, and going full circle historically, return to the Hippocratic Oath, keep [subjects] from harm and injustice. Ethics and development have come together through tortuous paths. 31.4 PRECLINICAL DEVELOPMENT The aim of a clinical development program is to generate sufficient data to satisfy the regu- latory requirements for allowing the drug to be marketed. The endpoint of this process is to prove that the drug is safe and effective in humans. The doorway to testing the drug in humans in the United States is to generate an investigational new drug (IND) application. The initial animal studies to determine pharmacological effects are usually conducted using laboratory-scale drug synthesis. After the initial in vitro and in vivo tests have shown preclinical “proof of principle”, the scale-up process is begun. The initial scale-up is usu- ally between a few hundred grams to a kilogram, depending on the complexity of the synthesis and whether the synthetic route is scalable (i.e., chromatography steps can be accommodated in the scale-up or there are no potentially explosive steps that would pre- clude scale-up). For drugs that have little or no toxicity, the scale-up will have to be on the order of tens of kilograms, as the IND enabling toxicology evaluations may have to go to 100-fold the expected human dose. The next major event is the manufacture of good manu- facturing practice (GMP) material.

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