Development and Regulation of Drugs PDF

# DEVELOPMENT & REGULATION OF DRUGS ## PRINCIPLES OF CLINICAL PHARMACOLOGY Clinical pharmacology encompasses all aspects of drug actions in humans. It includes everything related to the use of drugs in humans, with a strong emphasis on evidence-based application. Additionally, clinical pharmacolog...

# DEVELOPMENT & REGULATION OF DRUGS ## PRINCIPLES OF CLINICAL PHARMACOLOGY Clinical pharmacology encompasses all aspects of drug actions in humans. It includes everything related to the use of drugs in humans, with a strong emphasis on evidence-based application. Additionally, clinical pharmacology addresses errors in treatment, adverse drug reactions, and the economic aspects of drug use and consumption (pharmacoepidemiology, pharmacoeconomics), among other areas. Clinical pharmacologists work in universities, research institutes, the pharmaceutical industry, drug regulatory agencies, government institutions, and secondary and tertiary healthcare facilities. ## DRUG DEVELOPMENT Drug development is a complex and lengthy process. Active substances are derived from medicinal plants, microorganisms, animal tissues, and through the modification of existing molecules. The discovery of new drugs begins with an idea or hypothesis, followed by the design and synthesis of a substance, preclinical (in vitro and in vivo) and clinical studies, the legal process for obtaining the necessary authorization to market the drug, and post-marketing studies. The entire drug development process involves three main stages: discovery, development, and marketing. ### Discovery This involves selecting a target for the drug's action (functional proteins such as receptors, enzymes, transport proteins) and identifying the key substance. During this process, the substance is optimized (enhancing its effect on the target molecule at the expense of other properties), and pharmacological profiling is performed. Potential drug candidates are selected based on various pharmacological properties. This process typically takes 2 to 5 years. ### Development This includes preclinical and clinical studies. #### Preclinical Studies These last approximately 1.5 years on average and involve pharmacodynamics and pharmacokinetics studies. The goal of pharmacodynamic studies is to discover the mechanism of drug action relevant to the proposed use, as well as other effects during its application. Pharmacodynamic investigations are conducted at the molecular level (enzymes, receptors, ion channels), the cellular level (tissue cultures, isolated tissues, and organs), and through systemic studies in experimental animals. The goal of pharmacokinetics studies is to examine the processes of absorption, distribution, metabolism, and excretion (ADME) of the drug from the organism of experimental animals. Toxicological studies (explained later) are also conducted, usually with single-dose administration. Afterward, the transition from small laboratories to pharmaceutical industry laboratories occurs, where the appropriate pharmaceutical form of the drug is developed. #### Clinical Studies These typically last between 5 to 7 years and consist of 4 phases in which the efficacy, side effects, and potential risks of the drug are evaluated in healthy volunteers and patients (see the table on the next page). * Phase I involves pharmacodynamic and pharmacokinetic studies, as well as assessing drug tolerability and side effects in healthy volunteers (20-100). * Phase II includes trials on a smaller group of patients (100-200) to determine efficacy ("proof of concept") and dosage, along with toxicity studies after repeated doses of the investigational drug. * Phase III is characterized by controlled clinical trials involving a large number of patients; double blind study. * Phase IV involves post-marketing surveillance, and monitoring safety of the new drug under actual conditions of use in large number of patients. ## Marketing of a Drug It must comply with the laws of the country where the drug is sold and distributed. This process is shaped by the pharmaceutical company that holds the license for the drug. The license (patent) gives the pharmaceutical company exclusive rights (monopoly) to manufacture and sell the drug, but this right expires after a certain number of years. After the patent expires, other pharmaceutical companies are allowed to produce bio-equivalent drugs, known as generics, which often lowers the initial cost of the drug. The data from studies must demonstrate that the drug will be useful, minimally toxic, and superior to already existing medications. A completely new drug is always welcome, but this is rare. The ideal drug should be specific, selective, non-toxic, and have a wide therapeutic index, though such a perfect drug does not exist in practice. | | In vitro studies | Animal testing | Clinical testing | Marketing | |---|---|---|---|---| | Biologic products | | | Phase 1 (20-100 subjects) | Phase 2 (100-200 patients) | | Lead compound | | Efficacy, selectivity, mechanism | Phase 3 (1000-6000 patients, double blind) | Phase 4 (Postmarketing surveillance) | | Chemical synthesis, optimization | | | Drug metabolism, safety assessment | Generics become available | | Years (average) | 0 | 2 | 4 | 8-9 | | | IND (Investigational New Drug) | | NDA (New Drug Application) | 20 (Patent expires 20 years after filing of application) | *FIGURE 5-1* The development and testing process required to bring a drug to market in the USA. Some of the requirements may be different for drugs used in life-threatening diseases (see text). *Source: Katzung Pharmacology* ## Toxicity Testing Toxicity studies are of great importance, and they must demonstrate how a potential drug causes damage in vitro and in experimental animals. These studies are long-lasting, performed on a large number of animals, using high doses, and are very expensive. There are several types of toxicity studies. ### Acute toxicity/single-dose testing: These are designed to assess the acute toxicity of a drug and determine its lethal dose (LD50). Testing must be done on at least 2-3 species of experimental animals (one must not be a rodent), with the drug administered at least twice (one route must be IV). ### Repeated-dose studies: These assess subacute, intermediate, and chronic toxicity. The study must be conducted on at least 2 species of experimental animals, with 3 doses (the first being the therapeutic dose, the second slightly higher than therapeutic, and the third dose which must cause death in the animals). The drug should be administered daily in a way that closely resembles therapeutic use in humans. The duration can range from 14 to 180 days, depending on the expected length of human drug use (e.g. single dose or up to 30 days). ### Reproductive performance studies: Done on 2 species on both sexes. They evaluate the drug's impact on gametogenesis, fertility, intrauterine growth (embryo- and fetotoxicity), delivery, postnatal development, late development, and effects on the second generation. ### Carcinogenic potential/oncogenicity studies: They are particularly important if the new substance is structurally similar to substances known to have carcinogenic potential. These studies last for the entire lifespan of the animal (usually 2 years). ### Mutagenic potential studies: These assess whether the drug causes genetic mutations. ### Local tolerance: These assess whether the drug damages mucous membranes, skin, subcutaneous tissue, or muscle. | Type of Test | Approach and Goals | |---|---| | Acute toxicity | Usually two species, two routes. Determine the no-effect dose and the maximum tolerated dose. In some cases, determine the acute dose that is lethal in approximately 50% of animals. | | Subacute or subchronic toxicity | Three doses, two species. Two weeks to 3 months of testing may be required before clinical trials. The longer the duration of expected clinical use, the longer the subacute test. Determine biochemical, physiologic effects. | | Chronic toxicity | Rodent and at least one nonrodent species for ≥ 6 months. Required when drug is intended to be used in humans for prolonged periods. Usually run concurrently with clinical trials. Determine same end points as subacute toxicity tests. | | Effect on reproductive performance | Two species, usually one rodent and rabbits. Test effects on animal mating behavior, reproduction, parturition, progeny, birth defects, postnatal development. | | Carcinogenic potential | Two years, two species. Required when drug is intended to be used in humans for prolonged periods. Determine gross and histologic pathology. | | Mutagenic potential | Test effects on genetic stability and mutations in bacteria (Ames test) or mammalian cells in culture; dominant lethal test and clastogenicity in mice. | *Source: Katzung pharmacology* ## Design The basic design of a study includes the selection of participants and a control group, the use of blinding methods, randomization, the inclusion of a placebo, and other important factors (such as the study location, whether the study is retrospective or prospective, assessment methods, and proper documentation). A placebo is an inactive substance designed to resemble the drug being tested as closely as possible. The purpose of using a placebo is to assess the pharmacological effect of the drug compared to the psychological effect. This is especially important when testing new analgesics, hypnotics, anxiolytics and other medication for conditions where evaluation is mostly subjective and based on the participant's personal experience. Clinical studies can be classified based on the time during which data is collected (prospective or retrospective), the patients involved in the study (one, two, or more groups of patients), and by type or phase (from Phase I to Phase IV). ## RATIONAL PHARMACOTHERAPY One of the key roles of clinical pharmacology is rational pharmacotherapy, which serves as the bridge between scientific research and practical therapy. Patients and the course of their diseases vary significantly, so treatment must be tailored to each individual patient—this is called individualization of therapy. Medications significantly contribute to reducing morbidity and mortality from various diseases, extending life expectancy, and improving the quality of life for both patients and healthy individuals. However, medications are also a major source of profit for the pharmaceutical industry. This has led to medicalization of society, where everyone is considered to have some illness needing treatment, and conflicts of interest, where doctors funded by pharmaceutical companies may recommend their drugs. Rational pharmacotherapy is any treatment based on the most up-to-date medical and pharmacological knowledge. The most valuable input for forming therapeutic approaches comes from well-designed clinical studies (prospective, randomized, double-blind, with a sufficient number of participants and appropriate controls). However, even the best available evidence is often insufficient due to the complexity of clinical practice (e.g., drug allergies), financial constraints, and lack of medication availability in pharmacies. Therefore, a physician must choose a list of medications that aligns with the best available evidence and the real-life situation. The rational pharmacotherapy process involves the physician-patient-drug triangle. The physician uses their expertise and available information to assess the risk-benefit ratio of a therapy, considering both the therapeutic benefits and the cost of the treatment. In terms of the patient, medical history, physical examination, lab tests, and other diagnostics help establish the correct diagnosis, which guides drug selection. However, drugs may also be used before a diagnosis is made to relieve symptoms, halt disease progression, or maintain vital functions. For the drug itself, key considerations include its pharmacodynamic and pharmacokinetic properties, side effects, and interactions with other drugs, endogenous substances, and food. It's important to note that a drug may be used even before all of its characteristics are known (for example, aspirin was used for almost 100 years before its mechanism of action was fully understood). Besides physicians, other healthcare professionals, such as pharmacists and nurses, as well as experts in drug analytics, contribute significantly to rational pharmacotherapy. The foundations of rational pharmacotherapy were laid by Wilcox, with questions such as: What? How much? When? In what form? What are the warnings? In other words, rational pharmacotherapy means using the right drug, for the right patient, at the right time, in the right dose, in the right way, and for an appropriate duration. At the beginning of rational pharmacotherapy is a thorough history and physical examination, before the diagnosis and prescription of appropriate therapy. Treatment can also begin immediately, even without a final diagnosis, or when the cause of the disease is not fully understood—this is called empirical therapy. Insisting on an accurate diagnosis before starting treatment may be harmful (as valuable time is lost), but starting treatment too early can complicate further treatment (e.g., selecting the wrong antibiotic). For initiating empirical therapy, therapeutic algorithms are very important. A good understanding of the disease's pathogenesis, as well as the knowledge of common etiological agents, is crucial for adequate pharmacotherapy. In some cases, it is possible to leave the patient without a drug, and it's important to resist the pressure to prescribe a medication when pharmacotherapy is not necessary (e.g., antibiotics are often not needed for uncomplicated upper respiratory tract infections). **Common mistakes in pharmacotherapy include:** * Failing to consider the patient's specific characteristics (e.g., drug allergies) * Making errors in writing, calculating, or interpreting drug information (e.g., name, dose, abbreviations) **Common problems when prescribing medications include:** * Prescribing an unnecessary medication * Prescribing an unnecessarily high dose * Prescribing a more toxic drug or one with serious side effects * Prescribing a drug that interacts with medications already being used, food, or dietary supplements * Writing prescriptions incorrectly or illegibly Mistakes in drug selection or evaluating therapeutic effects, even minor ones, can cause irreparable harm to the patient. Problems may include the failure of the applied therapy leading to disease progression, or serious adverse drug reactions. ## PHARMACOVIGILANCE Pharmacovigilance is the science and practice dedicated to detecting, assessing, understanding, and preventing adverse effects and other drug-related problems. **The key responsibilities of pharmacovigilance include:** * **Identification and quantification of new adverse drug reactions (ADRs)**: this involves recognizing previously unreported or unexpected side effects. * **Identification of subgroups of patients at special risk**: some patient populations might have a higher likelihood of developing ADRs due to factors such as genetics, age, or pre-existing conditions. * **Continuous monitoring of drug safety**: this ensures that the risk-benefit ratio of a drug remains acceptable during its use. * **Detection of errors in drug prescribing and administration**: pharmacovigilance helps identify mistakes that could affect patient safety. * **Detailed evaluation of the pharmacotoxicological properties of drugs**: this includes understanding the harmful effects of drugs on different systems of the body. * **Detection of significant drug interactions**: some interactions only become apparent when a drug is used on a large scale. * **Providing healthcare professionals with appropriate information on ADRs**: ensuring that doctors, pharmacists, and other healthcare workers are well-informed about potential risks. **Key terms in pharmacovigilance:** * **Adverse Drug Reaction (ADR)**: any harmful and unintended response to a drug, occurring at doses normally used in humans for the prevention, diagnosis, treatment, or modification of physiological functions. * **Serious Adverse Drug Reaction**: a harmful response to a drug that results in death, is life-threatening, requires hospitalization, prolongs existing hospitalization, causes disability, or results in congenital anomalies. * **Unexpected Adverse Drug Reaction**: an adverse reaction that is not described in the drug's labeling or investigator's brochure, including reactions with unexpected severity, intensity, or outcomes based on the drug's known pharmacological properties. * **Adverse Event/Experience**: any undesirable sign, symptom, laboratory finding, or disease temporally associated with the use of a drug, regardless of whether a causal relationship has been established. * **Serious Adverse Event**: an event that occurs during drug use and results in death, life-threatening conditions, hospitalization, or congenital anomalies, irrespective of a proven causal relationship. * **Adverse Interaction**: any undesirable reaction resulting from the altered pharmacological action or pharmacokinetics of one drug due to the concurrent administration of another drug, herbal product, or food. * **Drug Misuse**: the intentional overuse of a drug, either continuously or intermittently, leading to harmful physical or psychological effects. * **Off-label Use**: the use of an approved drug for an unapproved indication, dose, or method of administration. The occurrence of adverse effects can lead to the limitation or withdrawal of a drug from the market. It is essential, and legally required, to report all ADRs or adverse events involving medical products. In some countries, such as Serbia, ADRs are reported to the national regulatory agency (ALIMS). If a suspected ADR is confirmed, a signal is generated and reported to the World Health Organization (WHO) centre in Uppsala, Sweden. There, data is analyzed and shared with healthcare professionals globally. It is important to note that about 50% of all ADRs are preventable, which underscores the importance of efficient reporting. No pharmacologically effective drug is without adverse effects. The causes of ADRs are diverse and may be related to the drug itself (e.g., selectivity and specificity), the patient (e.g., age, sex, genetic factors, pathological conditions), or the physician (e.g., prescribing errors). Common sites of ADRs include the gastrointestinal system (35%), neuromuscular system (15%), endocrine system (13%), cardiovascular system (12%), as well as the skin, kidneys, blood, lungs, and other locations (5%). **Classification of ADRs by intensity:** * **Mild**: these reactions cause minor discomfort and are typically resolved with symptomatic treatment. * **Moderate**: these reactions are more bothersome and may partially improve with symptomatic treatment. * **Severe**: these reactions severely interfere with daily activities and are not alleviated by symptomatic treatment. **Classification of ADRs by frequency:** * **Very common**: Occurs in more than 10% of patients. * **Common**: Occurs in 1–10% of patients. * **Occasional**: Occurs in 0.1-1% of patients. * **Rare**: Occurs in 0.01–0.1% of patients. * **Very rare**: Occurs in fewer than 0.01% of patients. * **Unknown frequency**: When the exact frequency is not known. **Classification of ADRs by mechanism:** * **Type A reactions**: predictable based on the pharmacological properties of the drug and are dose-dependent. * **Type B reactions**: unpredictable and not related to the dose or the known pharmacology of the drug. | Type A Reactions (Augmented/Drug Effects) | Type B Reactions (Bizarre/Patient Reactions) | |---|---| | Pharmacological | Hypersensitivity reaction | | Dose dependent | Dose independent | | Predictable based on the pharmacological profile | Unpredictable | | More frequent (75% of cases) | Rarer (25%) | | Usually not that serious | Pretty serious | | Most discovered before registration of drug | Most discovered after registration of drug | | Relatively low mortality rate | Relatively high mortality rate | In addition to Type A ("drug effect") and Type B ("patient reactions”), there is also the introduction of Type C adverse drug reactions, also known as “statistical effects.” These reactions represent an increased incidence of a disease in individuals taking a specific medication compared to those not taking it. The disease already exists in the population, but the medication increases its incidence. These reactions are serious and relatively common. Examples include thromboembolic complications following the use of certain contraceptives and the development of peptic ulcers as a result of NSAID therapy. An extended pharmacological classification of adverse reactions includes the following subtypes: * **A (augmented)** - an enhanced pharmacological effect * **B (bizarre)** - strange or unusual reactions * **C (chronic)** - chronic effects (e.g., iatrogenic Cushing's syndrome after prolonged prednisone use) * **D (delayed)** - delayed effects (e.g., craniofacial malformations in newborns whose mothers used tretinoin during pregnancy) * **E (end of treatment)** - effects that occur after stopping the medication (e.g., angina pectoris after sudden withdrawal of beta-blockers) Underreporting of ADRs is influenced by two groups of factors: * **Patient-related factors**: lack of clear symptoms, psychological disorders, memory issues, the patient not associating the ADR with the medication, the patient believing they should endure the effects, fear of informing the doctor for fear of being labeled neurotic, or the doctor not being willing to listen. * **Physician-related factors**: passivity or disinterest, as well as intentional avoidance of addressing the issue (fear of being contradicted by other experts or guilt for causing the patient's suffering). ## SOURCES OF DRUG INFORMATION There are several types of resources from which physicians and other healthcare professionals can gather information about drugs. These include textbooks, monographs, pharmacopoeias, drug registries, review papers, original research articles, manufacturer data, and electronic databases. ### Pharmacology Textbooks They are often the first source of drug information for medical students and doctors in training. They provide knowledge of general principles such as pharmacokinetics, pharmacodynamics, adverse effects, and drug interactions. Textbooks are easy to use and widely available. However, they can become outdated quickly, lack detailed information due to space constraints, and their authors may not be experts in all the topics covered. ### Monographs They are scientific or professional essays that focus on a specific topic (such as a group of drugs or a single drug). They are usually written by experts and serve as reliable sources of information, but their currency must be considered. Monographs are often part of pharmacopoeias and drug handbooks. ### Pharmacopoeias They are official publications that establish guidelines for the preparation of drugs, testing, and confirming the identity of substances used in drug production, quality control, and storage. The standards and guidelines listed in pharmacopoeias have the force of law. Some countries publish their own national pharmacopoeias or adopt translations of international pharmacopoeias (e.g., the European Pharmacopoeia, The International Pharmacopoeia). For example, the Yugoslav Pharmacopoeia 2000 consists of two parts: the first part (general) contains data on the drug manufacturing process, which is more important for pharmacists than physicians, and the second part contains drug monographs listed alphabetically. Today, pharmacopoeias are primarily intended for pharmacists and those involved in drug production, rather than physicians. ### Drug Registries They have become the dominant source of drug information, given the widespread use of finished pharmaceutical products. They are usually published annually and include data on all drugs registered in a specific country for a given year. In Serbia, the ALIMS issues the "Yellow Registry." The registry contains information on indications, adverse reactions, dosages, contraindications, based on the data provided by manufacturers and relevant scientific literature. The 2009 Registry is divided into four sections: 1. Information detailing each drug, organized alphabetically by brand name. 2. An alphabetical list of international non-proprietary drug names. 3. Drugs grouped by the Anatomical-Therapeutic-Chemical (ATC) classification. 4. Drugs grouped by manufacturers. The ATC classification is the official drug classification system in the country. Each drug is assigned a code with 7 alphanumeric characters that reflect five levels of classification. *Example: Diazepam has the code N05BA01:* * N: Main anatomical group (drugs acting on the CNS) * 05: Main therapeutic subgroup (psycholeptics) * B: Therapeutic subgroup (anxiolytics) * A: Chemical/therapeutic subgroup (benzodiazepines) * 01: Specific substance (diazepam) The registry also includes a list of traditional herbal medicines and homeopathic products, which are regulated by law. Additionally, it identifies drugs with specific effects on psychomotor coordination. Drugs marked with an empty triangle have a potential effect on psychomotor abilities, while those marked with a filled triangle have a proven strong effect (referred to as "trigonics"). Drugs marked with a paragraph symbol are from the opioid group ("paragraphics") and are subject to special legal regulations (duplicate prescriptions, legally defined doses, record-keeping of every prescription). The registry also contains other useful information such as the vaccination calendar, insulin tables, and tables of daily vitamin requirements. ### Scientific papers Allow physicians to apply the latest evidence-based knowledge in diagnosis and treatment to achieve the best outcomes with the least costs. Promotional materials from pharmaceutical companies (e.g., various pamphlets), although based on scientific data, should be approached with caution, and the information should be cross-referenced with other unbiased sources. ### Electronic databases (e.g., PUBMED, MEDLINE, EMBASE) allow for the search of a vast number of scientific and professional journals based on keywords in the internet era. It's essential to consider the currency and quality of the papers found. There are also various websites dedicated to searching drug information (e.g., RxList in the U.S.), and nearly all of the aforementioned registries, handbooks, guidelines, and algorithms are available in electronic form. ## EVALUATION OF DRUG USE The evaluation of drug use is a continuous process that spans all phases of clinical drug trials. It begins as soon as the efficacy of a drug has been confirmed in preclinical trials, with the central focus being Phase IV clinical trials. These trials are conducted in humans, which requires strict adherence to rules to ensure the highest possible protection for study participants. Key areas of drug use evaluation include pharmacoepidemiology and pharmacovigilance. **Objectives of drug studies in Phase IV:** * Clarification of issues from previous phases: comparing the drug's effects with other drugs, conducting cost-effectiveness studies, assessing patient compliance and quality of life, understanding the mechanisms of action, discovering and evaluating new indications, determining application methods, dosage, and treatment duration, etc. * Investigating drug interactions with other medications. * Application in a large number of patients to confirm efficacy and safety. * Identifying rare and dangerous adverse effects. * Comparing previously obtained results from specialized institutions with results from broader clinical practice. * Studying the clinical picture of overdose and possibilities for prevention and treatment. * Evaluating the risk-benefit ratio for a given drug. **Types of clinical studies in Phase IV:** * Descriptive studies. * Observational studies (prevalence studies, case studies, cohort studies). * Controlled clinical trials. ### Pharmacoepidemiology Studies the use and effects of drugs in large populations or specific population groups. It combines the principles and methods of epidemiology with areas of clinical pharmacology. This approach allows for predicting the drug's effect in patients based on data and research on its use in large numbers of people. One of the most important aspects is the study of drug safety, including adverse effects and drug interactions, after a drug has been placed on the market (post-marketing surveillance). Pharmacoepidemiological research falls into the category of observational studies, where there is no strict control of parameters, and they are conducted as cohort studies or case studies. Additionally, pharmacoepidemiology also monitors drug consumption and performs cost-benefit analysis. ### Pharmacovigilance Involves the system of monitoring the safety of drug use and tracking adverse effects in the general population. *For further details, refer to previous questions on Phase IV clinical studies, pharmacovigilance, and related topics.*