Introduction
In this book, the term "drug" specifically denotes traditional pharmaceuticals and biopharmaceuticals that effectively address clinical concerns It explores the development of ethical drugs requiring physician prescriptions, emphasizing small molecule drugs that feature novel chemical compounds known as new chemical entities (NCEs) or new molecular entities (NMEs) Additionally, the text highlights biologicals, focusing on proteins produced through large-scale cultivation of microbial or mammalian cells.
The development of new drugs is a complex, time-consuming, and costly process, typically taking 10 to 15 years and requiring approximately $1.3 billion This intricate endeavor necessitates the collaboration of experts from various fields, including medicinal chemistry, molecular biology, pharmacology, and regulatory science The challenges associated with advancing a drug from the research phase to market approval are underscored by the fact that most potential drugs fail to reach the final stages of development.
1 J.R Turner, New Drug Development, DOI 10.1007/978-1-4419-6418-2_1,
C Springer Science+Business Media, LLC 2010
Origin and Goals of the Book
In preparing this book, I aimed to embody the principles I teach my students: clarity, conciseness, and contemporary relevance The content reflects current trends in drug development and includes curated Further Readings at the end of each chapter for deeper exploration of these topics Ultimately, the assessment of clarity and conciseness rests with you, the reader.
This article offers a concise overview of new drug development, focusing on pharmaceutical clinical trials It emphasizes two crucial aspects: the importance of study design and statistical analysis, which are closely interconnected, and the effective implementation of a clinical trial's protocol, which governs all study elements While primarily addressing clinical drug development programs, it also briefly touches on other facets of the drug development lifecycle to provide context The content is designed to be introductory, and additional readings are suggested for those interested in exploring specific topics further.
The Discipline of Statistics
This book presents statistical concepts in a conceptual manner rather than focusing on computations, aiming to demystify the term "statistics." By the end, readers should find statistics less intimidating and more relevant, alleviating any negative associations they may have with the subject.
Statistics, as an integral discipline, plays a crucial role in various activities related to clinical trials.
• Identifying a research question that needs to be answered.
• Deciding upon the design of the study, the methodology that will be employed, and the numerical representations of biological information (data) that will be collected.
This study protocol outlines the design and methodology for data collection, ensuring that all necessary methodological considerations are addressed to achieve high-quality data for future statistical analysis.
In developing a comprehensive statistical analysis plan, it is essential to identify the statistical techniques that will be employed to effectively describe and analyze the data This plan should be crafted in conjunction with the study protocol to ensure alignment and clarity throughout the research process.
A Lifecycle Perspective on Drug Development
The analysis of the data involves a thorough examination of its variation to determine whether there is strong evidence supporting the safety and efficacy of the drug This process requires evaluating both the statistical significance of the results and, crucially, their clinical relevance.
• Presenting the results of a clinical study to a regulatory agency in a clinical study report and presenting the results to the clinical community in journal publications.
Statistics plays a crucial role in making informed decisions, as study design and statistical analysis are closely interconnected The design of a study dictates the analysis methods employed after data collection Additionally, experimental methodology and operational execution are vital to ensuring the highest quality of data The primary aim of experimental methodology is to gather high-quality data, while operational execution focuses on maintaining this quality Without high-quality data, statistical analyses cannot yield optimal information, which ultimately affects decision-making quality.
In new drug development research, it is essential to plan statistical analyses during the study design phase to ensure effective data collection Additionally, understanding the ultimate goal of obtaining approval from the relevant regulatory agency is crucial from the beginning Regulatory agencies offer extensive guidance on conducting and reporting drug development research, which should be thoroughly reviewed and considered throughout the entire process.
1.4 A Lifecycle Perspective on Drug Development
The process of new drug development, as defined by bringing a new drug to mar- keting approval by a regulatory agency, can be represented by a three-stage model including
• Drug discovery and drug design (the latter term will be explained in due course);
This book comprehensively covers all stages of drug development, with a particular focus on two critical areas: manufacturing, explored in Chapter 15, and postmarketing surveillance, discussed in Chapter 16 By examining these topics, the book provides a lifecycle perspective, tracing a new drug's journey from its inception to its widespread therapeutic application.
Design, Conduct, and Analysis
Compelling Evidence
Compelling evidence refers to statistically significant results from analyses, but it is a misconception to say these results "prove" something Statistically significant findings represent probabilistic statements rather than absolutes The philosophy of scientific inquiry emphasizes that theories cannot be proven, only disproven Science is an investigative process, with disciplines like physics, chemistry, and biology employing the scientific method Theories generate hypotheses that must be testable and disprovable When repeated testing fails to disprove a theory, compelling evidence accumulates, suggesting the theory may have merit However, it is essential to remain open to future investigations that could potentially refute the theory.
Drug Discovery
Drug discovery encompasses the process from identifying a therapeutic need in a specific disease area to selecting the most promising drug candidate that can safely provide the desired therapeutic effect This candidate can either be a small molecule or a biological agent, such as a protein or nucleic acid The activities involved in drug discovery differ significantly between small molecule drugs and biological therapies.
Clinical development programs for biologicals follow a structured approach Once a drug candidate is identified, it transitions into the drug development phase, where regulatory oversight for both nonclinical and clinical research becomes crucial The process for obtaining marketing approval closely resembles that of other drug types, ensuring consistency in regulatory governance throughout the development stages.
Nonclinical Development Programs
The terminology surrounding nonclinical versus preclinical research often sparks debate, particularly regarding nonhuman animal testing This research is essential for obtaining regulatory approval to test new drugs in humans While the term preclinical suggests that such testing occurs exclusively before human trials, a significant portion actually takes place after initial human administration, especially when early tests indicate a favorable safety profile Consequently, the term nonclinical has gained traction to encompass all research involving nonhuman animals, reflecting its broader application in the drug development process.
After a drug candidate is chosen through the drug discovery process, it enters nonclinical development, which is essential for ensuring safety and efficacy before human trials While the ultimate aim is to achieve human pharmacological therapy, understanding the nonclinical aspects is crucial for designing ethical and effective clinical studies Efficacy refers to the intended therapeutic effects of the drug, and nonclinical research encompasses in vitro, ex vivo, and in vivo testing to gather vital data on safety, dosage, and administration methods.
Clinical Development Programs
Ethical Conduct
Treating subjects in clinical trials in an ethical manner is of paramount importance. Several fundamental ethical principles guide drug development research in clinical trials, including
Clinical equipoise refers to the ethical principle that exists when there is no conclusive evidence indicating that a new drug is either more or less beneficial than an alternative treatment This principle is crucial for conducting clinical trials, which involve administering an investigational drug to some participants while providing a control treatment, often a placebo, to others For a trial to proceed, researchers must operate under the assumption that all treatments being tested hold equal value, ensuring that participants are fully informed and consent to the possibility that the investigational drug may not outperform the control Ultimately, while a trial may reveal that the new drug is safer and more effective, it must begin with the genuine belief in the equivalence of both treatment options.
• Respect for persons This principle necessitates that investigators give potential participants all pertinent information about the study and answer any questions.
Informed consent is secured when a willing participant voluntarily agrees to join a study without any coercion, requiring their written permission or that of a parent or guardian It is essential to safeguard individuals with impaired decision-making abilities and ensure the confidentiality of all information collected throughout the study process.
The principle of beneficence mandates that research studies must be designed with scientific rigor, ensuring that any potential risks are justified by the anticipated benefits, particularly in terms of knowledge gained that can positively impact a significant number of individuals.
Justice in clinical trials mandates the equitable distribution of burdens and benefits among participants Historically, researchers have often targeted easily accessible populations, like prison inmates and nursing home residents, which raises ethical concerns It is crucial to ensure that vulnerable groups are not exploited in research settings.
1.8 Clinical Development Programs 7 be deliberately chosen for participation in clinical trials when nonvulnerable populations would also be appropriate The benefits of participation, such as access to potentially life-saving new therapies, should be available to all, includ- ing those not historically well represented such as women, children, and members of ethnic minorities.
Derenzo and Moss (2006) captured the importance of ethical considerations in all aspects of clinical studies in the following quote:
Every element of a clinical trial carries ethical implications that are inseparable from its scientific goals Failing to integrate ethical considerations with the overall study design indicates a misunderstanding of the essential principles of research involving human subjects Properly conducted trials must recognize that ethical and scientific factors are deeply interconnected.
Different Studies in a Clinical Development
The safety profile of an approved drug is as crucial as its efficacy, with initial evaluations typically conducted in healthy adult subjects during first-time-in-human (FTIH) studies The terminology used in this context, such as "healthy volunteers," can be misleading, as all clinical trial participants are volunteers, and using "volunteer" solely for FIH trials may imply that participants in other trials are not Furthermore, the term "normal" can unintentionally suggest that subjects in other trials are abnormal in ways unrelated to their disease or condition Therefore, referring to participants as healthy adult subjects helps avoid these misunderstandings.
In the later stages of drug development, if initial FIH trials are successful, the investigational drug is tested in larger trials involving a greater number of subjects with the relevant medical condition The primary aim of these extensive trials is to gather statistically and clinically significant evidence regarding the drug's efficacy, alongside further assessments of its safety and tolerability Ultimately, these trials seek to answer specific research questions related to the drug's effectiveness.
After a drug receives marketing approval, ongoing data collection focuses on its safety and effectiveness, distinguishing between efficacy and effectiveness Efficacy is assessed in controlled clinical trials with 3,000 to 5,000 participants, but once marketed, the drug is prescribed to hundreds of thousands of patients from diverse backgrounds who may use it less rigorously This broader usage can lead to the emergence of rare side effects that were not identified during trials, as these adverse reactions are statistically unlikely to appear in smaller studies Therefore, it is crucial to evaluate the drug's therapeutic benefits in this larger, real-world context to ensure its overall effectiveness.
Postmarketing surveillance is essential for assessing the safety and effectiveness of marketed drugs By monitoring reports of adverse reactions, it compiles comprehensive safety data, ensuring that all individuals within a target disease population are adequately protected from potential drug-related harms Additionally, this process evaluates the actual performance of marketed drugs across different identified populations.
Clinical literature publishes reports on a drug's safety and efficacy, providing essential evidence for clinicians and research scientists regarding its beneficial use This information supports evidence-based medicine, allowing healthcare providers to tailor treatments to the unique needs of individual patients Consequently, patients benefit from the insights gained in clinical trials, as their clinicians review medical journal articles to determine the most effective treatments, collaboratively deciding on the best options for their care.
Manufacturing
The manufacturing of drugs and biologicals plays a crucial role in the drug development process, necessitating careful consideration of varying quantities required at different stages Due to the complexity of this topic, determining the optimal placement for discussing manufacturing considerations posed a challenge Ultimately, it was decided to address this important subject in Chapter 15.
Once a drug candidate is identified during the drug discovery phase, it must undergo nonclinical and clinical trials to obtain marketing approval In clinical trials, the drug must be administered in specific forms, such as tablets or injections, which involves a highly complex manufacturing process If the drug molecule cannot be effectively administered, manufactured, and marketed in a transportable form with a stable shelf-life, it remains impractical for widespread clinical use, regardless of its potential benefits.
Manufacturing processes in new drug development vary by stage, beginning with small laboratory-scale production of the drug As the clinical development progresses, the required quantities increase significantly Ultimately, for the drug to be marketed, full-scale commercial manufacturing becomes necessary.
Definitions of Clinical Research and Clinical Trials
Clinical Research
Clinical research encompasses a broad range of investigative activities, characterized by its complexity and diversity According to the National Institutes of Health (NIH), this field is defined on their official website.
The NIH defines human clinical research as patient-oriented research involving direct interaction with human subjects or their materials, excluding in vitro studies that cannot be linked to living individuals This research encompasses various areas, including mechanisms of human disease, therapeutic interventions, clinical trials, and the development of new technologies Additionally, human clinical research includes epidemiologic and behavioral studies, as well as outcomes and health services research.
Turner and Durham (2009) provided a more succinct definition:
Clinical research comprises any research undertaken with the intent of improving the care provided to patients (p 196).
This definition encompasses nonclinical research, which aims to enhance care for human patients Additionally, findings from these studies can also benefit veterinary medicine.
In vitro, ex vivo, and in vivo animal studies are essential preliminary steps before conducting clinical trials, as highlighted in Chapter 4 Nonclinical information often appears on the labeling of approved drugs to assist prescribing physicians in determining the suitability of a medication for their patients When human data is lacking, this nonclinical data can be valuable in guiding the decision-making process for both physicians and patients.
Clinical research encompasses studies conducted during the drug discovery phase as well as postmarketing surveillance, highlighting its integral role in the entire drug development lifecycle This perspective is essential for the discussions presented throughout this book.
Clinical Trials
The NIH has defined a clinical trial on its web site (http://www.nih.gov) as
A prospective biomedical or behavioral research study involving human subjects aims to address specific inquiries regarding biomedical or behavioral interventions, including drugs, treatments, devices, or innovative applications of existing therapies.
Piantadosi (2005) provided a more succinct definition:
A clinical trial is an experiment testing a medical treatment on human subjects (p 16).
Operational Execution
After optimizing study design and experimental methodology, executing the clinical trial as outlined in the protocol becomes a significant task, necessitating a diverse team of professionals from various clinical research specialties While the first edition of this book did not cover operational execution, Chapter 7 in this edition focuses specifically on this topic, and additional operational considerations are explored in several other chapters.
The Central Importance of Biological Considerations
This book, while it includes terms like study design and statistics, fundamentally focuses on biology, particularly through the lens of clinical research and trials The term "clinical" emphasizes the biological significance of a drug's effects, as these studies address clinically relevant issues that are closely tied to biological needs The primary driver of new drug development is the identification of unmet medical and biological needs Consequently, the aim is to create biologically active drugs that are safe, well-tolerated, and effective in treating or preventing conditions that are clinically significant for patients.
The term "reasonably safe" may appear unusual at first, yet all medications come with potential side effects Thus, the primary objective is to achieve a favorable benefit–risk ratio, a concept that will be explored extensively in the following chapters.
The relevance and importance of the regulatory environment cannot be overemphasized.
Introduction
Goals of the ICH
The ICH has several goals, including
Establishing a forum for constructive dialogue between regulatory authorities and the pharmaceutical industry is essential to address the varying technical requirements for marketing approval across the European Union, the United States, and Japan This collaboration aims to facilitate the timely introduction of new drugs, ultimately enhancing their availability to patients.
Facilitating the adoption of innovative technical research and development approaches is essential for modernizing existing practices These enhanced methods aim to optimize the use of animal, human, and material resources while ensuring safety is not compromised.
• Monitoring and updating harmonized technical requirements leading to a greater mutual acceptance of research and development data.
• Contributing to the protection of public health from an international perspective.
• Encouraging the implementation and integration of common standards of doc- umentation and submission of regulatory applications by disseminating harmo- nized guidelines.
The ICH has developed numerous guidance documents to assist sponsors in drug development research and documentation, focusing on key areas such as drug safety, efficacy, and quality For more comprehensive information, please visit the ICH website at http://www.ich.org.
The Food and Drug Administration
The Code of Federal Regulations
The Federal Register is a daily publication by the government, excluding federal holidays, that contains important regulations Annually revised, the Code of Federal Regulations (CFR) organizes the permanent rules from the Federal Register into a comprehensive codification.
50 titles, each of which is further divided into subchapters, parts, subparts, and sec- tions The FDA regulations are in Title 21 of the CFR, commonly referred to as
21 CFR Individual regulations have more detailed identifiers; 21 CFR 310.3, for example, provides the code’s definition of a new drug.
cGMP, cGLP, and cGCP
In the realm of new drug development, three key acronyms are frequently encountered: Good Manufacturing Practice (GMP), Good Laboratory Practice (GLP), and Good Clinical Practice (GCP) These practices ensure that each stage of drug development adheres to established regulations and guidelines The "c" in each acronym signifies "current," and the term cGxP may be used to collectively reference all three practices This highlights that, over time, best practices may evolve between regulatory updates Thus, while the latest guidelines represent the official position, it is advisable to adapt to these evolving practices as necessary.
Regulatory Aspects of New Drug Development
New drug development and approval are subject to numerous regulatory requirements that necessitate extensive laboratory testing, nonclinical work, and clinical trials before a sponsor can submit a registration request for human use It is crucial that all procedures and results are meticulously documented, as regulatory authorities consider research undocumented if it lacks proper documentation.
Nonclinical and clinical development processes are essential for drug approval Nonclinical studies are submitted to the FDA through an Investigational New Drug Application (IND), which is evaluated to determine if clinical trials can commence Upon completing the clinical development program, all findings are compiled in a New Drug Application (NDA) or a Biological License Application (BLA) Successful review of these submissions leads to the approval of the drug for marketing.
The new drug development and approval process includes several principal steps:
• FDA review of the IND.
• Preparation and submission of an NDA or a BLA following clinical research.
• FDA review and approval of the NDA or BLA Following an initial review, the agency may ask for more documentation before granting marketing approval.
The highly abbreviated descriptions in the following sections are intended to serve as an introduction to, and an indicator of the importance of, the regulatory environment.
2.6 The Investigational New Drug Application 15
Sponsor and Regulatory Agency Responsibilities
Sponsors and regulatory agencies play crucial roles in the approval and oversight of drug products The marketing approval process represents a formal agreement between the sponsor and the regulatory agency, with detailed conditions outlined in the prescribing information Any proposed changes by the sponsor must be communicated to the agency, often requiring new approval The responsibilities of the regulatory agency encompass ensuring compliance and maintaining drug safety.
• Approving the clinical trial application.
• Approving drugs that have been scientifically evaluated to provide evidence of a satisfactory benefit–risk ratio (the balance between the therapeutic advantages of receiving the drug and possible risks).
• Monitoring the safety of the marketed drug.
In severe instances, a marketing license may be revoked due to several factors, such as the lack of sufficient supplementary information in the prescribing details following reported adverse reactions, as well as non-compliance with regulations related to drug manufacturing.
The sponsor’s roles and responsibilities include
• Keeping all pertinent documentation related to the drug up to date and ensuring it complies with standards set by the current state of scientific knowledge and the regulatory agency.
• Collecting, compiling, and evaluating safety data and submitting regular reports to the regulatory agency.
• Taking rapid action where necessary This includes withdrawal of a particular batch of the drug or withdrawal of the entire product if warranted.
The regulatory environment plays a crucial role in the drug development process, highlighting the essential interactions between sponsors and regulatory agencies before and after a drug's marketing approval Regulatory affairs professionals maintain ongoing communication with these agencies to ensure compliance and facilitate the development of safe and effective medications.
The Investigational New Drug Application
Review of the Investigational New Drug
When submitting an Investigational New Drug (IND) application, sponsors must clearly outline the objectives of their clinical development program The initial submission should include a general investigational plan detailing the studies to be conducted in the first year, with further updates providing additional information The FDA's review process encompasses various evaluations, including medical/clinical, chemistry, pharmacology/toxicology, and statistical assessments.
Medical officers, primarily physicians, conduct reviews to assess the safety of clinical protocols in an Investigational New Drug (IND) application Companies typically initiate an IND with one study and subsequently add new protocols, which are scrutinized to ensure that subjects are protected from unnecessary risks and that the study designs yield relevant data on the drug's safety and efficacy Federal regulations mandate that proposed Phase I trials focus primarily on safety As the initial IND is amended to include new protocols and report completed studies, the FDA must be kept updated on all gathered data For Phase II and Phase III trials, reviewers must also verify that the studies maintain sufficient scientific quality to support marketing approval.
Chemists play a crucial role in evaluating the Chemistry and Manufacturing Control (CMC) sections of the Investigational New Drug (IND) application, which focus on drug identity, manufacturing processes, and analytical methods It is essential that drug manufacturing procedures guarantee the compound's stability and consistent production to high-quality standards The IND must clearly outline any differences in chemistry and manufacturing between the investigational drug intended for clinical use and the drug used in animal toxicology trials that supported the safety for clinical studies If discrepancies exist, the sponsor must address their potential impact on the safety profile of the clinical drug product.
This review, conducted by pharmacologists and toxicologists, assesses animal testing results to correlate drug effects in animals with potential human impacts The Investigational New Drug (IND) application must detail the pharmacological effects and mechanisms of action observed in animal studies, along with pharmacokinetic information covering absorption, distribution, metabolism, and excretion Additionally, an integrated summary of the drug's toxicological effects observed in vitro and in animal models is essential If certain animal models are deemed irrelevant due to species specificity or other factors, sponsors are advised to consult with the agency regarding alternative toxicological testing.
The Center for Drug Evaluation and Research (CDER) houses multiple offices, including the Office of Pharmacoepidemiology and Statistical Science, which encompasses the Office of Biostatistics A key responsibility of the Office of Biostatistics is to create statistical and mathematical methods aimed at improving the drug review process across various domains.
• Chemical testing and product quality assessment and control.
The Office of Biostatistics has spearheaded the creation of key guidance documents, notably ICH E9 on Statistical Principles in Clinical Trials and ICH E10 regarding the Choice of Control Groups in Clinical Trials Sponsors are encouraged to adhere to these essential guidelines.
In the IND statistical review, study protocols are assessed differently based on the study phase Phase I studies, focused on safety, may not undergo a statistical review, while protocols evaluating efficacy, especially with large sample sizes, are more likely to be reviewed Most Phase III trials receive thorough statistical evaluations, as they aim to provide strong evidence of both safety and efficacy, necessitating careful attention to design, methodology, and analysis Statisticians are particularly interested in various aspects of the protocol during this review process.
• Does the design facilitate collection of data that are appropriate for addressing the study objectives and reduce the potential for bias?
• Are the primary endpoints relevant?
• Have the criteria that will be used to determine efficacy been precisely specified?
• Have the randomization schedule and all aspects of methodology (operational and measurement) been detailed adequately?
• Have sample size estimates been conducted appropriately and is the study powered as needed?
The New Drug Application
Statistical Review of the New Drug Application
The article discusses the key aspects of the statistical review process for New Drug Applications (NDAs) Unlike Investigational New Drug (IND) submissions, NDAs include completed studies along with their data analysis and interpretation The FDA's evaluation of an NDA centers on assessing the compelling evidence of the drug's safety, efficacy, and manufacturing capabilities to determine its market approval Statistical reviewers are crucial in this process, as they examine the Statistics and Clinical Data sections and provide insights on other relevant sections as needed.
Statisticians reviewing a New Drug Application (NDA) assess the statistical significance of the data to inform medical officers about its generalizability to the broader patient population They analyze any deviations from the original protocols submitted in the Investigational New Drug (IND) application and evaluate the overall quality of the collected data Additionally, all amendments to the clinical study protocol are scrutinized to determine how these changes, along with any undocumented deviations, may have impacted the study's findings.
Access to electronic study data enables FDA statisticians to replicate reported analyses and perform additional analyses as needed, ensuring they can make informed decisions regarding drug approval for marketing.
The Office of Biostatistics offers valuable insights through statistical reviews and evaluations conducted by their statisticians during the review of New Drug Applications (NDAs) After drug approval, these reports are made publicly available, providing a glimpse into the thought processes of FDA statisticians.
Cartwright AC, Matthews BR (Eds), 2009, International Pharmaceutical Product Registration. New York, NY: Informa Healthcare.
Mathieu M, 2008, New Drug Development: A Regulatory Overview, 8th Edition Waltham, MA: Parexel.
Tobin JJ, Walsh G, 2008, Medical Product Regulatory Affairs: Pharmaceuticals, Diagnostics, and Medical Devices Weinheim, Germany: Wiley-VCH.
Weinberg S, 2009, Guidebook for Drug Regulatory Submissions Hoboken, NJ: Wiley.
For a drug molecule to elicit a response, it must precisely match the three-dimensional geometry of the target receptor's active site upon entering its microenvironment.
Introduction
Small Molecule Drug Candidates
Recent advancements in biomedical science and a significant increase in understanding molecular chemistry and biology have led to a more technology-driven approach in small molecule drug discovery As their name suggests, small molecule drugs possess a small molecular size and weight.
A typical definition would be molecules whose molecular weight is less than 700 daltons (Da).
21 J.R Turner, New Drug Development, DOI 10.1007/978-1-4419-6418-2_3,
C Springer Science+Business Media, LLC 2010
In contemporary drug development, the foundation often lies in understanding the molecular structure of the biological target, typically a macromolecule known as the target receptor This knowledge enables the application of molecular technologies to identify drugs with suitable molecular structures for achieving the desired pharmacological effects The concept of drug design has emerged, which involves modifying the structure of existing chemical molecules to enhance their pharmacokinetic profiles or synthesizing new, related molecules for specific pharmacological advantages.
The primary objectives of drug discovery and design are to identify a lead compound, which serves as the top candidate for nonclinical testing, and to optimize this molecule through a process known as lead optimization This involves finding closely related compounds or making chemical modifications to the lead drug to determine the most suitable candidate for advancement in the drug development process.
Biopharmaceutical Drug Candidates
Biopharmaceuticals, often referred to as biologicals or macromolecule drugs, represent a significant category of therapeutic agents with advantageous properties Unlike small molecule drugs, these biologicals possess substantially higher molecular weights, exemplified by monoclonal antibodies, which can exceed 140,000 Da.
Various terms for (classes of) large molecule drugs are used in various docu- ments These include biological, biopharmaceutical, and biotechnology medicines.
In this book, the term biological is used synonymously with the term large molecule drug to differentiate it from small molecule drugs Discussion of biologicals starts in Section3.5.
Overview of Pharmaceutics, Pharmacokinetics,
Drug Receptors
Drugs influence cellular activities by binding to specific macromolecules, primarily located on cell membranes, thereby altering their biochemical functions This interaction is defined by the term "receptor," which refers to the components of a cell that engage with a drug, triggering a series of biochemical events that result in the drug's effects The receptor concept has been invaluable in molecular biology, enhancing our understanding of biological regulation and becoming a key focus in pharmacodynamics and the molecular mechanisms of drug action.
The receptor concept has important practical consequences for the development of new drugs:
• Receptors largely determine the quantitative relations between the concentration of a drug in the body and its pharmacological effects.
Receptors play a crucial role in determining a drug's selectivity, as the molecular size, shape, and electrical charge influence its binding affinity to specific receptors The diversity of chemically distinct receptors means that a new drug's chemical structure can significantly affect its affinity for various receptor classes, leading to changes in both therapeutic and toxic effects.
Receptors play a crucial role in mediating the effects of pharmacological agents, including both agonists and antagonists Agonists bind to receptors and activate them, leading to a physiological response, while antagonists also bind to receptors but do not trigger any signal This binding prevents other potential drugs from activating the receptor and producing a physiological effect, thereby inhibiting the action of agonists Although our focus is on developing new drugs that act as agonists, the significance of pharmacological antagonists in clinical medicine cannot be overlooked.
Most receptors are complex proteins, which exhibit a remarkable diversity in shape, size, and mobility compared to other molecules This variety, along with their specific shapes and electrical charges, likely contributed to the evolution of their function as receptors The most well-studied receptors are regulatory proteins that facilitate the actions of endogenous messengers like neurotransmitters and hormones, playing a crucial role in mediating the effects of many effective therapeutic agents.
The Pharmacodynamic Phase
Pharmacodynamics examines how drugs affect the body, such as their ability to lower blood pressure This process begins when a drug molecule reaches the microenvironment of its target receptor, allowing it to dock and exert its pharmacological effects The successful binding of a drug to its receptor is facilitated by the complementary molecular geometries of their functional groups, enabling favorable interactions between their electrons This interaction is crucial for triggering the desired biological effects of the drug.
The Pharmacokinetic Phase
Pharmacokinetics examines how the body influences a drug from the moment it is absorbed until it arrives at the receptor site For a drug to effectively exert its pharmacodynamic effects, it must reach its target receptor, often located deep within the body This requires the drug molecule to navigate through various physiological barriers to successfully reach its intended destination.
The characteristics of a molecule significantly affect its ability to reach target receptors, influencing the drug's pharmacokinetic profile and its pharmacodynamic effects Among the various routes of drug administration—such as oral, rectal, intravenous, subcutaneous, intramuscular, intra-arterial, topical, and inhalation—oral administration is the most common for small molecule drugs Consequently, this chapter primarily discusses the oral route, while noting that biologics are usually administered through injections directly into the bloodstream.
The chemical structure of a drug significantly impacts its effectiveness in achieving biological effects by interacting with target receptors Four key pharmacokinetic processes determine the concentration of an administered drug.
Metabolism plays a crucial role in how humans interact with various foreign compounds, known as xenobiotics, that we encounter daily These substances can enter the body through ingestion, inhalation, or skin contact, with processed foods being a significant source of these xenobiotics.
3.3 Medicinal Chemistry 25 contain a large amount of xenobiotics Fortunately, the body is very good at getting rid of these foreign substances, and it has sophisticated methods for neutralizing and eliminating them However, these sophisticated neutralization and elimination methods are problematic in the case of drugs, which are also xenobiotics and are therefore subject to the same actions by the body.
The liver's metabolism and the kidneys' excretion are crucial for the body's neutralization and elimination processes In drug discovery and design, it is essential to consider these mechanisms; a drug with a promising pharmacodynamic profile may fail to be clinically effective if it cannot reach its target receptor in the appropriate chemical form required for the desired therapeutic effect.
The Pharmaceutical Phase
The pharmaceutical phase refers to the period from drug administration until its absorption into the bloodstream For orally administered drugs to be effective, they must possess specific properties The active pharmaceutical ingredient (API), which is responsible for the drug's pharmacodynamic effects, typically constitutes a small fraction of the tablet's composition In addition to the API, tablets contain various excipients—nonpharmacologically active ingredients that serve essential roles in facilitating the delivery of the API to its target receptors.
The pharmaceutical scientist needs to consider the drug product’s formulation.
A tablet serves as a sophisticated drug delivery system, ensuring the safe transport of drug molecules to their target receptors Excipients play a crucial role in protecting the drug from chemical degradation during its journey from the mouth through the gastrointestinal tract Additionally, these excipients facilitate smooth passage through the gastrointestinal tract and aid in the release of the active pharmaceutical ingredient (API) for absorption in the small intestine, marking the point at which the drug is released from its formulation.
Medicinal Chemistry
Drug Molecules
A molecule is the fundamental unit of a substance, maintaining its chemical identity Atoms within a molecule are organized into functional groups, which influence the molecule's properties One notable functional group is the carboxylic acid group, denoted as “–COOH,” comprising a carbon atom, two oxygen atoms, and a hydrogen atom These functional groups play a crucial role in determining the chemical and physical characteristics of molecules.
Drug-like molecules are characterized by their relatively low molecular weight and the presence of one or more functional groups attached to a rigid structural backbone This rigidity is essential to maintain the molecule's shape, allowing the functional groups to be positioned in a specific three-dimensional arrangement for effective interaction with macromolecules The term "drug-like molecule" refers to those that could potentially bind to receptor sites on macromolecules, while "drug molecule" is used when a specific binding affinity is confirmed A receptor that shows potential as a therapeutic target is initially termed a "druggable target," and once its utility is established, it is classified as a "drug target."
Macromolecules, Receptors, and Drug Targets
Endogenous macromolecules, such as proteins and nucleic acids, are prevalent in mammalian cells and serve as crucial drug targets due to their role as receptors These receptors possess specific sites that allow drug molecules to attach, with the three-dimensional shape of the drug's functional unit designed to fit the receptor's structure.
Structure–Activity Considerations and Drug–Receptor Interactions
Understanding a molecule's structure is crucial for grasping its activity, as a drug molecule consists of various molecular fragments arranged in a specific three-dimensional configuration This atomic arrangement dictates the drug's physico-chemical, shape, stereochemical, and electronic properties, which are essential in determining whether the administered drug will effectively reach its target receptor and interact with it successfully.
Physiochemical properties play a crucial role in determining a drug's solubility and pharmacokinetic characteristics These properties significantly influence the drug's ability to reach its target area within the body, which may be far from the administration site For instance, effective penetration of the blood-brain barrier is essential for a drug to bind to its receptor sites in the brain.
The shape and stereochemical properties of a drug significantly impact its pharmacodynamic phase and interaction with target receptors These characteristics define the structural arrangement of the drug molecule's constituent atoms, ultimately influencing how the molecule approaches and binds to its target receptor.
The electronic properties of a drug molecule play a crucial role in its pharmacodynamic phase, influencing how the drug interacts with its target receptor These properties, shaped by the distribution of electrons within the molecule, dictate the nature and strength of the binding interaction The energetic exchange between the drug and receptor is vital, as it determines the intensity of the biological signal generated, ultimately governing the physiological effects of the drug.
The introduction of computer-aided structure–activity modeling has popularized the concept of a pharmacophore, which is essential for understanding drug–receptor interactions and is a key element in the drug design process A pharmacophore is characterized by its ability to define the essential features that enable a drug to interact effectively with its target receptor.
The concept discussed is not a specific molecule or a direct association of functional groups; instead, it serves as an abstract representation that captures the shared molecular interaction capabilities of a group of compounds in relation to their target structure.
• It describes the essential (steric and electronic) function-determining points necessary for an optimal interaction with a relevant target.
• It can be considered as the highest common denominator of a group of molecules exhibiting a similar pharmacological profile and which are recognized by the same target receptor.
A toxicophore refers to a specific arrangement of geometric and electronic characteristics within a drug molecule's functional group that interacts with unintended receptors, leading to undesirable biological responses or side effects This concept is often associated with the terms off-target and anti-target receptors.
The metabophore is a crucial component of a drug, representing the three-dimensional arrangement of atoms that determines its metabolic properties Drug molecules are considered multiphores, composed of various biophores and biologically functional groups situated on a structural backbone, usually an organic molecule.
For a drug molecule to elicit a response upon entering the target receptor's microenvironment, its three-dimensional geometry must align with the active site's geometry Thus, the pharmacophore must be accurately spatially and geometrically positioned as the drug approaches the receptor.
Molecules can consist of the same set of atoms arranged in various ways, known as isomers Conformational isomerism refers to the process where a molecule transitions between different shapes while retaining its physical properties These varying shapes can affect how well the molecule interacts with receptor sites, with some configurations being ideal for interaction, while others may be less effective or completely unsuitable.
Cheminformatics, Bioinformatics, and Computer-Aided Molecular Design
Bioinformatics
Bioinformatics plays a crucial role in deciphering cellular functions by integrating extensive data from various sub-disciplines of molecular and cell biology This integration is essential for developing cellular models that facilitate hypothesis generation for experimental testing, as noted by Bader and Enright (2005).
Bioinformatics is essential for addressing the challenges of data integration and modeling, as it facilitates the development of databases, visualization tools, and analytical software These resources are crucial for effective data assimilation, ensuring that results are accessible and valuable for solving biological questions.
The rise of modern computers and clusters has enabled in silico testing, a method that uses extensive computer modeling to identify molecules likely to interact effectively with target receptors before synthesis This approach evaluates various aspects of the molecule, such as its ability to reach and bind to the drug receptor, as well as the specifics of the binding interaction Additionally, in silico development assesses potential binding with nontarget receptors to prevent unintended effects and adverse events.
Advancements in understanding receptor macromolecule structures have enabled researchers to utilize computer-assisted molecular design, integrating bioinformatics and cheminformatics to create lead compounds from the ground up This innovative approach allows for efficient in silico three-dimensional docking simulations, where potential drug molecules are tested for binding with receptors Consequently, this method streamlines the identification of safe and effective drug candidates, making the drug discovery process faster, more cost-effective, and less complex compared to traditional methods.
As a lead compound is optimized, enhancing the features of the pharmacophore to elicit a more energetic therapeutic interaction with the receptor is important.
Modifying toxicophores is essential to reduce or eliminate side effects of drugs Alongside pharmacodynamic and toxicodynamic factors, pharmacokinetic aspects must also be considered The objective is to alter the metabophore to decrease the drug's rapid metabolism in the liver and its swift excretion by the kidneys, enhancing the molecule's potential to achieve its intended pharmacodynamic effects.
Understanding the structure and function of receptor macromolecules is crucial in pharmacodynamics, alongside the exploration of beneficial drug molecules With advancements in receptor structure knowledge, researchers can now design lead compounds from the ground up, increasing their chances for successful development and optimization.
Biologicals
Molecular Genetics and Proteins
In higher organisms, including humans, biological information flows systematically, with DNA encoding instructions that are transcribed and translated by RNA before being delivered to protein assembly machinery While DNA is widely recognized, RNA, which plays a crucial role in life processes, has not received the same level of attention Notably, DNA and proteins do not communicate in the same language, leading to confusion after Watson and Crick identified DNA's molecular structure in 1953.
The longstanding belief that the first life-form was based on a DNA molecule presents a fundamental contradiction, as DNA cannot self-assemble and relies on proteins for its formation This raises the question of which originated first: proteins, which lack a method for information duplication, or DNA, which can replicate but only with the aid of proteins This dilemma suggests an unsolvable problem, highlighting the interdependence of DNA and proteins in the origins of life.
RNA, or ribonucleic acid, serves as both a DNA equivalent by storing and replicating genetic information and a protein equivalent by catalyzing essential chemical reactions It is believed that the earliest life-forms were entirely RNA-based, and RNA continues to play a vital role in our cellular systems today Remarkably, RNA translates the genetic information encoded in DNA into a format that proteins can interpret and utilize effectively.
In the mid-1970s, the understanding of genes shifted dramatically with the 1977 discovery that individual genes in higher organisms, or eukaryotic cells, consist of multiple DNA segments interspersed with noncoding DNA This led to the identification of RNA splicing, an intricate editing process that removes noncoding sequences and joins the relevant segments to form messenger RNA (mRNA) The mRNA then plays a crucial role in synthesizing amino acids, which are assembled in specific sequences to produce proteins, ultimately translating the genetic instructions encoded in DNA.
Proteins play crucial biological roles, particularly as drug receptors and enzymes, with enzymes being the largest class of proteins Most enzyme names end in “-ase” and serve as catalysts for nearly all chemical reactions in living organisms Consequently, enzymes facilitate almost every step in biological reactions by significantly lowering the activation energy needed for these processes.
Protein Structures
Proteins are intricate structures that extend beyond just a linear sequence of amino acids To better understand their complexity, a hierarchical model has been developed, which aims to simplify their description and identify structural similarities This model consists of three distinct levels.
The primary structure of a protein is defined by its sequence of amino acids, known as residues, which are linked by chemical bonds to form chains Initially, this chain is shapeless and biologically inactive Secondary structures arise from short segments of these residues, resulting in distinct shapes that contribute to the protein's overall architecture Common forms of secondary structures include α-helices, β-sheets, β-turns, and loops, with some regions remaining unclassifiable as random coils The final shape of these secondary structures is influenced by a complex interplay of attractive and repulsive forces among various parts of the protein, making the prediction of secondary structures from the linear amino acid sequence a significant challenge in molecular biology.
The tertiary structure of a protein refers to its overall three-dimensional shape, which is determined by the spatial arrangement of secondary structures Various classes of tertiary structures exist, with advanced classification systems considering common topologies, motifs, or folds Notable examples of these tertiary folds include the α/β-barrel, the four-helix bundle, and the Greek key Importantly, any alteration in the protein's structure can significantly affect its biological activity.
Recombinant DNA Technology
DNA molecules are vast, presenting significant challenges in the early stages of molecular biology To comprehend the specific functions of certain DNA segments, researchers needed to isolate those segments and produce sufficient quantities for analysis As noted by Watson (2004), this process was complex and required innovative techniques.
We required a molecular editing system that includes molecular scissors to cut DNA into manageable segments, a glue pot for manipulating those segments, and a duplicating machine to amplify the isolated pieces.
In the early 1970s, recombinant DNA technology emerged, enabling the editing of DNA through the use of enzymes Restriction enzymes cut DNA at specific locations, generating predictable fragments with defined sequences, while DNA ligases join these fragments to form recombinant DNA molecules This innovative technology allows for the production of millions of copies of a specific DNA sequence through molecular cloning, facilitating experimental studies in the laboratory.
Recombinant Proteins As Drugs
Recombinant DNA technology led to the first commercial biological drug applications, notably the production of human growth hormone and insulin To meet the high demand for insulin, it was initially sourced from human cadavers and animals Human insulin consists of two amino acid chains, with the A chain playing a crucial role in its structure.
Human insulin consists of 21 amino acid residues in the A chain and 30 in the B chain, with structural similarities preserved in bovine and porcine insulin, featuring amino acid substitutions at five key locations (A8, A10, B28, B29, B30) This biological resemblance allows for the functional use of animal-derived insulin in humans; however, the risk of contamination is significant As a result, the extraction of insulin from animals has declined significantly since the introduction of recombinant DNA technology, which enables the production of recombinant insulin.
Human insulin can be biosynthetically produced using Escherichia coli, a cost-effective prokaryotic host cell, due to the simplicity of the insulin protein Insulin analogs such as insulin lispro and insulin aspart have minor amino acid substitutions compared to human insulin, with insulin lispro differing at positions B29 and B30, while insulin aspart has aspartic acid replacing proline at position B28 These small structural changes significantly impact their function; for instance, the substitution in insulin aspart reduces molecular aggregation, allowing for faster dissociation and absorption in the body.
More complex recombinant human proteins are produced in various ways,including large-scale mammalian cell cultures Recombinant subunit vaccines, such
3.5 Biologicals 33 as hepatitis B and influenza vaccines, can be produced in yeast The organisms that carry the recombinant genes, and in which recombinant DNA drugs are produced,are called host organisms.
Discovery and Development
The discovery of most biologicals stems from a deeper understanding of the body’s molecular mechanisms Although nature has perfected protein structures for their biological functions, these structures are often not ideal for pharmaceutical use The process of protein drug discovery begins with known biomolecules, aiming to modify them to achieve specific desirable traits and activities To enhance these pharmaceutical characteristics, genetic engineering is utilized to re-engineer the protein structure.
The discovery process for biologicals, primarily human proteins, is generally more efficient than that for small molecule drugs, leveraging our growing understanding of molecular functions in the body Unlike traditional drug development, screening and lead optimization are unnecessary, significantly reducing the risk of immune responses to foreign molecules Furthermore, advancements in genomics and proteomics are expected to enhance this process, leading to the identification of previously unknown proteins that could serve as potential biologicals.
The development of biological drugs faces challenges similar to those of small molecule drugs, particularly in the accuracy of in vitro and in vivo studies to predict human physiological responses Additional hurdles include effectively targeting the drug within the body and managing short plasma half-lives Most approved biologicals require injection, which can hinder patient adherence due to the pain and inconvenience of frequent administration Alternative delivery methods, such as oral, nasal, or pulmonary routes, have largely failed for protein biologicals due to gastrointestinal enzyme inactivation and low permeability caused by their large molecular size.
Assessing the pharmacokinetics of protein biologics presents unique challenges compared to small molecule drugs, necessitating more resources While these biological drug candidates adhere to general pharmacokinetic principles, their resemblance to endogenous molecules complicates the evaluation of pharmacokinetics and the pharmacokinetic/pharmacodynamic relationships.