Drug Development 1 PDF

Drug Development 1 Module 01: Principles and Perspectives II Peter Glenn Y. Chua, MD-MBA | Asynchronous TABLE OF CONTENTS I. INTRODUCTION................................................................................ 1 II. HOW ARE NEW MOLECULES DISCOVERED....................................... 1 A...

Drug Development 1 Module 01: Principles and Perspectives II Peter Glenn Y. Chua, MD-MBA | Asynchronous TABLE OF CONTENTS I. INTRODUCTION................................................................................ 1 II. HOW ARE NEW MOLECULES DISCOVERED....................................... 1 A. WHY ARE NEW DRUGS NECESSARY?........................................... 1 B. WHO ARE THE STAKEHOLDERS?...................................................1 C. WHERE ARE THE DRUGS COMING FROM?...................................3 D. WHO ARE DEVELOPING NEW DRUG PRODUCTS?........................3 E. WHERE DOES INSPIRATION COME FROM?...................................4 III. HOW ARE LEADS DEVELOPED INTO A PRODUCT............................. 4 A. DRUG DISCOVERY AND DEVELOPMENT CYCLE............................ 4 B. BASIC RESEARCH.......................................................................... 4 C. DRUG DISCOVERY.........................................................................5 D. MILESTONES IN VACCINOLOGY AND VACCINE DESIGN................6 E. CLINICAL STUDIES.........................................................................7 F. POST APPROVAL SURVEILLANCE.................................................. 8 QUESTIONS......................................................................................... 9 ANSWER KEY.......................................................................................9 RATIONALE..........................................................................................9 I. INTRODUCTION ● World Health Organization (WHO) Essential Medicines and Health Products Perspective ○ Guides the overall perspective for drug development ○ Built on three pillars ▸ Access ▸ Innovation ▸ Regulation II. HOW ARE NEW MOLECULES DISCOVERED A. WHY ARE NEW DRUGS NECESSARY? ● Improved understanding of disease yields new targets for diagnostics and therapeutics ○ These targets may have been previously unforgettable ▸ Monoclonal antibodies and recent biotechnology methods (e.g. arrays, filtration technologies) allow better selection of molecules ● Existing therapies are more toxic, more difficult to administer, and/or more expensive to produce ○ Goal: Develop a drug with less side effects and can be manufactured more efficiently ● In the case of infectious diseases, the target is continuously evolving ○ Antimicrobials/antibiotics become less effective over time ○ Bacteria, fungi, and other targets of antimicrobials are developing new ways of resisting/neutralizing the drugs used against them YL6:01.25a Figure 1. Metallo-β-Lactamase-1 Figure 1 ● Metallo-β-Lactamase-1 ○ One of the dreaded enzymes ○ Able to neutralize a wide variety of currently available antibiotics ● It is the presence of this type of enzymes/evolutionary response to antibiotics that urges us to discover new and better antibiotics. B. WHO ARE THE STAKEHOLDERS? ● Who are the players involved in the development and discoveries of new drugs, vaccines, and antibiotics? ○ It is an entire ecosystem consisting of the public, private, and professionals ▸ Academic Research Institutions/units ⎻ ASMPH ▸ State research units ⎻ National Institute of Health in the USA ▸ Financers, venture capital, established banks ⎻ Interested in keeping the health of their clients ▸ Regulatory Agencies ⎻ Food and Drug Administration ⎻ National Medicines Regulatory Agency ▸ Clinical Research Organizations ▸ Professionals ⎻ E.g. pharmacists, physicians TG11: Aceret, Agatep, Bautista, Bolaños, Dacalanio, Legaspi, Lui, Nuñez, Sacro, Sy, Tayag, Viernes CG03: Austria, De Guzman, Galope, Gregorio, Llanes, So, T., Sotelo, Suarez, Uy, D. 1 ⎻ Can draw on other innovators to bring more products into the market sooner ○ Contract Research Organization ▸ Provides expertise in the conduct of clinical trials ▸ Includes the negotiation the regulatory gauntlet: the standard right for all drug products seeking to be used in the market on patients ▸ Drugs have to be assured for safety and effectiveness INTERNATIONAL COUNCIL FOR HARMONIZATION (ICH) Figure 2. Stakeholders in Drug Development ● A collaborative environment among all these actors/stakeholders is what is needed to generate new molecules that will end up as medicines ○ The public sector, through the government, is expected to provide sufficient incentives for the private sector to invest ○ Current situation in the Philippines ▸ It is highly discouraging investing biopharmaceuticals given what we have for a regulatory and fiscal regime for the industry ▸ The public sector may say: “let's allow forthemarket to compete for the best initiatives out there” ⎻ But if the ecosystem is not in place and if its overall tenor is not conducive to innovation, then it might be a case of overregulation ⎻ Should there be more space for innovations so that new drugs and initiatives can grow? Figure 3. Drug Development Process ● The process of drug development is lengthy ○ Starts with research pre-discovery and pre-clinical studies ○ Followed by early-stage drug development followed by late-stage drug development ○ Still have regulatory approval before it can be released to the market via Phase IV studies ● Roles are assigned all along this process of bringing new medicines and therapeutic agents to the market (Figure 3) ○ Pharmaceutical companies ▸ Exert overall responsibility in the development of the new drug ○ Academia ▸ Provides the basic research that will provide the necessary knowledge and science for the early-stage development ○ Smaller and agile biotechnology companies ▸ Leverage on available basic research and can be more responsive compared to larger pharmaceutical companies ▸ Advantages as smaller companies: ⎻ Can be more innovative YL6:01.25a Drug Development 1 ● National medicine’s regulatory agencies are guided by ICH ● Harmonization aims to minimize the delay due to redundancies of drug development and regulatory approval ○ Without ICH, a drug developed by the US would need to conduct a separate clinical trial for other countries (e.g. European Union, Japan) ▸ Note that clinical trials are very expensive and highly resource intensive ▸ Hence, data generated from one regulatory agency can be considered as supporting information for regulatory approval of another regulatory agency ○ Avoids redundancies ▸ Ensures that clinical trial information is shared uniformly among the regulatory actors worldwide ● Pioneered by the European Community in the 1980s in developing a single market for pharmaceuticals ○ The pharmaceutical industry is a highly protected industry ▸ It is quasi-nationalized: developed countries have flag bearer for pharmaceuticals, something that other countries like the Philippines should strive for Table 1. Regulatory and Industry Members of the ICH Regulatory Members Industry Members US FDA EC-EMA MHLW/PMDA EFPIA JPMA PhRMA Health Canada Swissmedic ANVISA China FDA Korea MFDS BIO IGBA WSMI ● Among the more recent members of the ICH are regulatory agencies from Canada, Switzerland, Brazil, China, and Korea (Table 1) FOOD & DRUG ADMINISTRATION (FDA) ● Serves as the national medicines regulatory agency ● Under the umbrella of the Department of Health (DOH) which is the health regulatory agency of the Philippines ● FDA issues policies and guidelines observed by pharmaceutical companies in the Philippines: ○ Market authority ○ Approval for licensing facilities ○ Registration of products ● 1963: Established by RA No. 3720 ● 2009: Charter was updated by RA No. 9711 ● The FDA is either the primary or supporting implementing agency of the following laws: ○ RA 9502: The Universally Accessible Cheaper and Quality Medicine Act of 2008 ○ RA 6675: The Generics Act of 1988 ○ RA 9211: The Tobacco Regulation Act of 2003 ○ RA 7394: The Consumer Act of the Philippines, 1992 2 ○ RA 10611: The Food Safety Act of 2013 ○ RA 10354: The Responsible Parenthood and Reproductive Health Bill of 2012 ○ PD 856: The Code of Sanitation of the Philippines, 1975 ● The FDA is frequently cited as the agency responsible for ensuring the safety of food ○ The 1987 Constitution shows that this is one of the responsibilities of the DOH ○ Bureau of Food and Drug: old name of FDA ▸ Presence of the FDA is constitutionally mandated ○ Safety of food and drugs is observed C. WHERE ARE THE DRUGS COMING FROM? ● Medical technology ○ US, Germany, Japan: leading sources of patent grants from 2000-2015 ▸ Leading in innovation in terms of medical technology, specifically in: ⎻ Imaging ⎻ Diagnostics ⎻ Therapeutics ⎻ New needles ⎻ New pump devices ⎻ New filters ○ Philippines: not innovative ▸ Belongs to the lowest category in new patents for medical technology and pharmaceuticals D. WHO ARE DEVELOPING NEW DRUG PRODUCTS? ● First half (see Figure 4) dominated by American companies ○ 6 out of 10 are from the US (e.g. Johnson & Johnson, Pfizer, Merck & Co., AbbVie, Amgen, Abbott Laboratories) ○ The rest are European ▸ Roche and Novartis from Switzerland ▸ Novo Nordisk from Norway ▸ Bayer from Germany ▸ GlaxoSmithKline from United Kingdom ▸ Sanofi from France ● Second half (see Figure 5) still dominated by American companies ○ Other than American companies, there are also Irish companies and a Japanese company ranking 26th ● What does this say in terms of value for the pharmaceutical industry and value for human health? ○ Question whether if the Americans value human health a lot more and if they equate health with wealth ▸ Inquire whether health is just another reflector of being wealthy and powerful ○ Even if the pharmaceutical industry is dominated by American companies, American health outcomes are being eclipsed by countries with poorer circumstances and fewer resources like Cuba ○ The presence of larger pharmaceutical companies in the country does not guarantee better health status of its citizens ▸ The Japanese, French, and Swiss have longer and better lives even though they only have a few large biopharmaceutical companies ○ Is population size a factor for this matter? ▸ If so, then India and China should be a part of the list Figure 4. Medical Technology Patent Grants by the World Intellectual Property Organization (WIPO) for the period of 2000 to 2015 ● Pharmaceuticals ○ France, Switzerland, China: vibrancy in innovation for new molecules ○ US, Germany, Japan: still included in terms of innovation ○ Philippines: not innovative Figure 5. Pharmaceutical Patent Grants by the World Intellectual Property Organization (WIPO) for the period of 2000 to 2015 ● In both medical technology and pharmaceuticals ○ US, Germany, Japan: innovative YL6:01.25a Drug Development 1 Figure 6. Top 13 Largest Pharmaceutical Companies in terms of Market Capitalization 3 III. HOW ARE LEADS DEVELOPED INTO A PRODUCT A. DRUG DISCOVERY AND DEVELOPMENT CYCLE Figure 8. Drug Discovery and Development Cycle Figure 7. Top 14 to Top 26 Largest Pharmaceutical Companies in terms of Market Capitalization E. WHERE DOES INSPIRATION COME FROM? ● Nature: ○ It is the best and most established source of new molecules. ○ Examples would include the following: ▸ Vinca alkaloids that come from periwinkle have been made into chemotherapeutic drugs ▸ Metformin, a drug commonly used to control blood sugar, comes from goat’s rue ▸ Concept of vaccination was inspired by cowpox blisters to prevent smallpox ▸ Quinine, the drug used to treat malaria, is the product of a bark that is native to South America ○ Nature continues to be the inspiration and the source for new molecules will into the future including antibiotics Active Recall Box 1. The process of drug development begins with: A. Innovation and partnerships B. Research pre-discovery C. Early stage drug development 2. T/F: US, Germany, France, Switzerland, China: front-runners in the vibrancy in innovation for new molecules. 3. T/F: The three pillars of the WHO Essential Medicines and Health Products Perspective include the following: activation, innovation, and access Answers: 1B, 2F, 3F YL6:01.25a Drug Development 1 ● The perspective that we need to have in the beginning is the drug discovery and development cycle (Figure 8): ● Begin with identifying a medical need through genetics and pathophysiology – this allows us to identify biomarkers and targets that can be studied to yield leads ○ How do we identify leads? Two strategies are present: ▸ Phenotypic drug discovery: ⎻ Historically, this is more active ⎻ Example: A person acquires a wound and is told to apply a paste made from leaves to control the inflammation. When the person followed the advice, the swelling went down, pus disappeared, and pain is reduced = the change in appearance and sensation is a phenotypic change ▪ This serves as the trigger for considering if the leaves used have an active ingredient that can fight infection, especially for wound ▪ Additionally, this serve as a jumping point for further drug discovery and development ▸ Target-based drug discovery ○ Studying the phenotype produced by potential drug sources and understanding the targets is part of fully defining the molecular mechanism of action. ○ There is the need to understand how these leads can bring about the desired outcome ○ When we optimize these leads, we bring it to the clinical trial process (phase 1 to 3). At the end of phase 3, the drug is registered and becomes ready for market access B. BASIC RESEARCH ● Molecular mechanism of action ○ Understanding this is important to optimizing the leads ○ Anchored on basic research for drug development and discovery ○ Involves many disciplines to allow for the study of disease models, cell culture techniques, tissue preservation, etc. ▸ Microbiological and ecological studies ⎻ Help understand infectious disease ▸ Chemistry and engineering disciplines ⎻ Develop techniques that allow study of animal and disease models, as well as tissues and molecules ⎻ Allow the study of cell culture and tissue preservation, as well as filtration and sterilization ▸ Animal models ⎻ Allow the study of anatomic, physiologic, and biochemical processes 4 ▪ There is a need for mammals such as mice, rates, rabbits, and monkeys to properly study anatomic, physiologic, and biochemical processes ▪ Good practices have been set to ensure that animals are not used wastefully and are treated humanely ⎻ Allows us to understand the disease in humans ▸ Disease models ⎻ Deepen the understanding of disease causation and progression ▸ Statisticians and data scientists organize available data to generate targets and leads ⎻ Organize available data to generate targets and leads ▪ Data can come from clinical trials done through the years ⎻ Relevant because they can identify previously missed leads as information is reviewed ▪ A strategy currently being used by pharmaceutical companies is looking back at past research to see if certain molecules have the potential to become new leads for other medical needs ○ An ecosystem or community of scientists engage in basic scientific research and engineering necessary to produce the body of knowledge from which leads are developed into drugs C. DRUG DISCOVERY LEAD DISCOVERY AND OPTIMIZATION FOR NATURAL PRODUCTS ● Recall: Phenotypic drug discovery is the historical main method of bringing new drugs to the market ● Lead discovery and optimization for natural products ○ Involve the isolation, identification, and characterization of active molecules (or principles) usually from plants ▸ However, fungi and animals have also been the source ○ Safety and quality procedures in handling and processing raw materials are established to ensure consistency and reliability ▸ A reliable product can be produced from crushed plants or plant extract ⎻ E.g. Artemisia annua is the natural source of antimalarial drugs artemether and artesunate ○ Methods for producing active principles for preclinical and clinical testing are optimized ● Targeted drug discovery ○ Based on more recent biotechnology methods, we are able to see potential targets based on genetic material and potential phenotypic expression ○ We can either have a structure-based drug discovery or ligand-based drug discovery ● Structure-based drug discovery ○ Oriented towards the receptor found on a cell membrane or organelle within the cell ○ Molecular dynamics (01.25, 2024) ▸ How the structure is folded ▸ How the structure behaves ▸ How ligands approach it ▸ E.g. receptor present in nuclear membrane cannot possibly be exposed to a ligand in the extracellular matrix ● Ligand-based drug discovery ○ Oriented towards the cytokine or signalling molecule that is in circulation throughout the body or cell ● Modeling involved in drug discovery includes: ○ Visualizing how proteins fold and interact based on their amino acid sequence ○ Looking at how proteins assume tertiary or quaternary structures given their primary structure ○ Considering what proteins can be produced from a nucleic acid sequence Take Note! ● Dr. Chua said this will not be asked in the exam. TARGET IDENTIFICATION AND VALIDATION ● An important step because not all targets identified by computer programs will yield something logical or directly observable ● Disease model ○ Identifies structures or ligands that can be targeted ● Computational methods allow assessment of genomes, transcriptomes, and/or proteomes ● Computer programs that identify structures that may be nonexistent and non-compatible with life are part of refining models for: ○ Prediction of protein structure ○ Interaction of nucleic acids and proteins ● Computer-Aided Drug Design (CADD) ○ Leverages on available libraries of molecular structure and interaction ○ Has gone significantly forward and is used by large pharmaceutical companies, but it still needs a lot of priming data for it to produce something more practical ● Lead discovery is still dominated at present by molecules discovered through phenotypic changes ○ E.g. historical method of seeing how a leaf applied to a wound is able to relieve infection or pain LEAD DISCOVERY AND OPTIMIZATION Figure 9. Targeted Drug Discovery/Design Principle YL6:01.25a Drug Development 1 ● Molecules are assessed by whether they can bind to the target and whether they elicit a cellular response ● Once molecules are assessed whether these molecules are inspired by nature or these are identified by a computer program based on a genetic sequence, these molecules need to be: ○ Refined and optimized before they can be brought to clinical trials 5 ○ Produced in sufficient quantities that it can be used in several hundred patients ○ Sufficiently clean so that adverse effects are minimized with animals and with humans ● There is significant effort involved in pre-clinical studies alone D. MILESTONES IN VACCINOLOGY AND VACCINE DESIGN ● ● ● ● ○ ED50 – median effective dose ▸ Dose that produces the desired effect in half the subjects ○ TD50 – median toxic dose ▸ Dose that produces a specified toxicity endpoint in half the subjects Classification of toxicity/adverse effects by time ○ Acute toxicity – observation of outcomes within two weeks ○ Subacute/subchronic toxicity – two weeks to three months ○ Chronic toxicity – six months or more Tolerance – dose-dependent toxicity ○ Single dose or acquired with repeated dose Safety and toxicity also focuses on additives, route of administration, dosage, frequency, drug interactions Toxicity endpoints that can be considered in assessing the safety of a drug ○ Cannot do these experiments on humans ▸ Need to do it on animals ▸ Animal experimentation is indispensable to drug development Table 2. Toxicity Endpoints in Assessing Safety Experiments Figure 10. Milestones in Vaccinology & Vaccine Design ● Idea of vaccination did not originate in Europe ○ Edward Jenner may be the “father of modern vaccination” but the concept of variolation (in this case: cowpox, variola to prevent smallpox) was already being done by the Mongols and Central Asians ● Variolation – exposing individuals to a milder form of disease ○ It was this practice that was acquired by the Turks, Arabs, and all of the Orientals that were considered as barbarians by Westerners ○ It was exactly this concept that inspired Edward Jenner to develop vaccines systemically and scientifically ● Modernized with many iterations ○ Currently, more than 50 vaccine-preventable diseases ▸ E.g., rabies, cholera, tetanus, polio, influenza, hepatitis B ● Recently: reverse vaccinology ○ Targeted drug design ○ Looking at DNA sequence to yield target for gene products ▸ Body cells will receive section of DNA for a gene that produces a protein ▸ Translated protein will be used as a target for lymphocytes to make antibodies ▸ Ex. RNA vaccines for Covid-19 ⎻ RNA vaccine delivers mRNA to body cells ⎻ Body cells will react to the product of the mRNA PRECLINICAL STUDIES ● Establishes the safety profile of a molecule ● Relevant pharmacokinetic and pharmacodynamic concepts ○ Absorption – how a molecule moves in to an organism ○ Distribution – how a molecule moves across anatomic spaces and compartments ○ Metabolism – how a molecule is changed within living tissue ○ Excretion – how the molecule moves out of the organism ● Toxicology profile with animal models ○ Animal testing under ethical and practical guidelines ▸ Rodent and non-rodent species ○ LD50 – median lethal dose ▸ Dose that kills half the subjects YL6:01.25a Drug Development 1 Endpoints Safety Pharmacology (in vitro, rodent, non-rodent) Behavior, function, physiology General Toxicology (rodent, non-rodent) Behavior, function, physiology, clinical biochemistry, and pathology Genetic Toxicology (in vitro, in vivo) Mutation, chromosomal changes Carcinogenicity (rodents) Non-genotoxic carcinogens Reproductive and Development Toxicology Fertility, pregnancy, fetal and peri-/post-natal development DRUG FORMULATION ● Bioavailability ○ The rate and extent to which an active moiety (molecule) is absorbed from the supplied form and made available at the site of action ○ Has a lot to do with ▸ Quality of drug preparation ▸ Route of administration ⎻ Intravenous: usually 100% bioavailable ⎻ Oral/inhalational: absorption varies depending on the technique or preparation of the product ● Bioequivalence ○ The bioavailability of a molecule compared to a generic, given everything else is the same ○ If a drug preparation is not the originator (i.e., a generic), there has to be an assurance that the generic drug is at least as effective as the originator ▸ Important for TB drugs, anti-retrovirals, antibiotics ● Additives ○ Ensure consistency in administration ○ Include fillers, binders, stabilizers, disintegrators, coating, color, and lubricants ● Dosage form ○ The physical state of the preparation 6 ○ A molecule can be administered as a powder for suspension, syrup, tablet, solution, gum, emulsion, cream ○ Considers route of administration (e.g., intravenous, intramuscular, intrathecal, topical, drops, spray) E. CLINICAL STUDIES ● Carefully conducted to protect human subjects ● Guided by current standards of practice ● ● GUIDELINES ● Current Standards of Practice (GxP’s or cGxP’s) ○ Prescribe ▸ Ethical and scientific guidelines ▸ Reporting mechanisms ● Good Clinical Practice (GCP) ○ Stems from the Declaration of Helsinki applies to the conduct of clinical trials involving human subjects ○ Important in upholding the rights of humans participating in clinical trials ● Good Tissue Practice (GTP) ○ Applies to the manufacture of biologic products (human cells, tissues, cellular- and tissue-based products) like stem cells ● Good Laboratory Practice (GLP) ○ Applies to non-clinical laboratory studies in the pre-clinical studies phase, with emphasis on animal testing ▸ Ensures that animals involved are humanely handled ● Good Manufacturing Practice (GMP) ○ Has direct impact on the safety and quality of products used on humans ▸ Part of this is Good Pharmacy Practice ○ Aims for consistency in the manufacture of products (primarily for human use) through control of the environment and documentation ▸ One of the control points of the regulatory agencies involved in drug manufacturing ▸ FDA looks at whether the facility is compliant with GMP ▸ ICH has an important document about this ● DSUR (Developmental Drug Safety Update Reports) ○ Inform the Health Regulatory Agency (HRA) of the safety and effectiveness of a drug while undergoing clinical trials ▸ Drug regulatory agencies are involved in the conduct of clinical trials from the very beginning ▸ Require a lot of pre-clinical information before giving the “go” signal to proceed with clinical trials ○ Submitted by the drug developing agent (e.g. large biopharmaceutical companies, contract research organizations, academic institutions) ▸ Submitted= periodically (semiannually, quarterly, or even monthly) ⎻ Depends on drug development pacing ⎻ In the case of COVID-19 vaccine development, DSURs are required weekly BIOETHICS ● “What happened before that must not happen again.” Historical Background ● Standards of practice and guidelines are based on bioethical principles (which in turn are based on historical experiences) ● Historical events that led to the development of modern bioethical principles: ○ Nazi human experiments during World War II ▸ Twin studies → checked if one twin is superior to the other YL6:01.25a Drug Development 1 ● ● ⎻ Aryan vs non-Aryan features (e.g. darker hair, darker eyes) ▸ Testing individuals by injecting poison ▸ Studies involving physical and psychological torture Universal Declaration of Human Rights (1948) ○ Post-World War II experiences led to countries realizing the value of human rights Nuremberg Code ○ Code of ethical research based on the trials of Nazi doctors/war criminals ○ Basis for the Declaration of Helsinki (1964), which inspired current good clinical practice Belmont Report (1978) ○ A response to the studies done to Tuskegee Airmen ▸ Tuskegee African-Americans were exposed to syphilis by the US army to see how it progresses ▸ Much of what we know of syphilis comes from this experiment ○ Ensures that clinical trials are conducted with full consideration of human rights International Ethical Guidelines for Biomedical Research Involving Human Subjects ○ Current guidebook for biomedical research ○ Made by the Council of International Organizations of Medical Science (CIOMS) in 1993 ○ Considers all previous documents and events, including recent medical research challenges ▸ Stanford prison experiment ⎻ Psychological torture for scientific study ▸ Thalidomide incident with pregnant women in Germany ⎻ Left infants born with no limbs ⎻ Drug was quickly made available to pregnant women after it has been approved for marketing Bioethical Principles ● The following principles shape good clinical practice ○ Respect for autonomy ○ Non-maleficence ○ Beneficence ○ Justice PHASE I CLINICAL TRIALS ● Mainly oriented towards safety and dosage ○ Side effects are described and documented ● First time that the new drug is tested in humans ○ 100 or fewer healthy humans are involved ○ Certain drugs should be tested on subjects with the diseases for which the treatment is being tested (e.g. testing anti-neoplastics for patients with cancer only) ● Before conducting the Phase I of the Clinical Trial, you need the approval of the HRA (Philippine FDA) ● At this point, a molecule is now known as the “Investigational New Drug” (IND) PHASE II CLINICAL TRIALS ● Safety and drug efficacy are the main priorities ○ Several hundred volunteers with the disease or condition of interest are involved ● IND is compared to a placebo and/or standard of care to establish causation and/or superiority ○ There is randomization - patients may receive either the IND or a placebo, but they don’t know which treatment arm they belong to (blinded) 7 ○ Treatment arm randomization is done by the clinical trial scientists ● Goal: To establish causation and/or superiority of the IND ● Administration schedules and dosage strength are established ● Based on filed applications, most INDs do not move past Phase II PHASE III CLINICAL TRIALS ● Safety, efficacy, and scale up are the main priorities ● Asking: “Can the manufacturing process cope with the increasing demand?” as it will require several thousand doses ○ Multi-center trials involving 1000 to 5000 patients (may be in different countries) ▸ E.g. Astrazeneca’s COVID-19 vaccine being tested in Brazil, South Korea, US, and UK ● Adverse reaction reporting systems are important because this is the phase where you will get drug interactions ● Volunteers are not as strictly screened as compared to Phase II as they are trying to approximate, more closely, market situations wherein the drug is exposed to a greater diversity of individuals ○ May have comorbidities ○ May be taking other concomitant medications ○ May be engaging in other diverse activities ● Labels and instructions are generated ○ Data are used to provide warnings ○ Provide instructions on how the drug may be given ○ May provide instructions on how to minimize side effects ● HRA approval is also required prior to conducting this stage Active Recall Box 4. This pertains to the guidelines derived from the Declaration of Helsinki which aim to uphold the human rights of humans participating in clinical trials. A. Good Laboratory Practice B. Good Tissue Practice C. Good Clinical Practice 5. T/F: HRA approval may be bypassed for Phase II trials as long as safety and efficacy is established in Phase I. 6. Aside from safety and efficacy, this is also one of the main priorities of Phase III trials which aims to determine whether the manufacturing process can cope with the increasing demand. Answers: 4C, 5F, 6 Scale Up F. POST APPROVAL SURVEILLANCE ● Anticipates risks that surface over time ● AKA Phase IV clinical trials HEALTH REGULATORY AND AGENCY MARKETING APPROVAL ● Marketing authorization allows the drug to be ready for market access ● Data from pre-clinical and clinical studies and DSURs are assembled into a technical document ○ Submitted to the US FDA for a new drug application (NDA) or biologics license application (BLA) ● The following must first be demonstrated: ○ Drug is safe and effective ○ Drug company is transparent (capable and consistent) ○ Manufacturing process is quality assured ● Once approved, the drug can now be sold in any place where YL6:01.25a Drug Development 1 the FDA has jurisdiction ● Must be compliant with GCP and GMP ROUTES OF EXPEDITED APPROVAL ● Fast Track for drugs in development treating serious conditions and filling an unmet medical need ○ E.g. COVID-19 Vaccine ● Breakthrough therapy for drugs in development that show substantial advantages over current therapy ○ E.g. monoclonal antibodies: enhance specificity and provide chemotherapeutic agents with targeting abilities allowing for a lower dosage of toxins ● Accelerated approval for drugs treating serious conditions or an unmet medical need based on a surrogate or intermediate clinical endpoint ○ Surrogate/intermediate clinical endpoint: a marker that can be measured that may correlate with a clinical benefit endpoint but that does not necessarily have a guaranteed relationship with it ○ E.g. cigarette consumption as a factor for lung cancer ▸ If an intervention can reduce cigarette consumption, it may be qualified for accelerated approval since it can reduce lung cancer incidence in the long term ● Priority review for drugs that show significant improvement in the safety or effectiveness of current treatment, diagnostics, or prevention of serious conditions HOW ARE LEADS DEVELOPED INTO A PRODUCT? ● The International Birth Date (IBD) refers to the date of the first marketing approval for any product containing the active substance granted to any company in any country in the world. ● A drug company that gets approval for an NDA or BLA is now the Market Authrorization Holder (MAH) ● DUSR data is carried over into a Periodic Drug Safety Update Report (PDRUR) or a Periodic Benefit-Risk Evaluation Report (PBRER). ○ Still submitted to the FDA even after the drug has been released to the market. ● PSURs are submitted every six (6) months for the first two or three years of approval. ● PSURs frequency may be adjusted to a longer periodicity as determined by the HRA. ○ Ex. Paracetamol = every 10 years ▸ Safety profile of paracetamol is quite stable ● Individual Case Safety Reports may be submitted anytime but are usually collated and included into a PSUR. ● Risk Evaluation and Mitigation Strategy anticipates that in the long term, the profile of benefits and risks change. ○ Drugs released in the market still have a lot of unknowns ○ Anticipate adverse reactions ○ Anticipate manufacturing recalls ● A Post-Authorization Safety Study (PASS) or Post-Authorization Efficacy Study (PAES) may be accomplished to re-establish benefit and risk profiles. ○ The former is for safety, the latter is for efficacy ● Direct Healthcare Professional Communication (DHPC) is intended to quickly disseminate safety information relevant to clinicians. ○ Directed towards clinicians and healthcare professionals ○ Ex. a particular batch of drug is known to be below the standard ▸ Clinicians are informed not to use the drug and coordinate with the regulatory agency 8 ○ In some regimes, the responsibility of drug recall belongs to healthcare professionals (including pharmacists) Active Recall Box 7. All of the following must be demonstrated prior to health regulatory an agency marketing approval, except: A. Drug is safe and effective B. Manufacturing process is quantity assured C. Drug company is transparent (capable and consistent) D. None of the above 8. PSURs are submitted every _____ months for the first two or three years of approval 9. This anticipates that in the long term, the profile of benefits and risks change. Answers: 7B, 8 six (6), 9 Risk Evaluation and Mitigation Strategy QUICK REVIEW QUESTIONS 1. The President of the Philippines recently appointed you as the Director-General of the FDA. You were then tasked to issue policies and guidelines observed by pharmaceutical companies in the Philippines. The following should be included in your key priority areas, except: A. Registration of products B. Efficacy and potency of drugs C. Market authority D. Approval for licensing facilities 2. Why is the establishment of the International Council for Harmonization (ICH) helpful among the stakeholders involved in drug discovery and development? A. A drug developed by the US would still need to conduct a separate clinical trial for other countries to facilitate global innovation, collaboration, and assessment. B. Data generated from one regulatory agency can no longer be considered as supporting information for regulatory approval of another regulatory agency to uphold the integrity and quality of pharmaceutical products. C. Clinical trial information is institutionally gatekeeped among the regulatory actors worldwide to nurture profitability, market capitalization, and intellectual property rights in the pharmaceutical industry. D. Delay due to redundancies involved in drug development and regulatory approval is further minimized. 3. T/F: All targets identified by computer programs will yield something logical or directly observable. 4. The idea of vaccination originated in Europe. The smallpox vaccine is from the cowpox virus. A. Only statement 1 is true B. Only statement 2 is true C. Both statements are true D. Both statements are false 5. As far as the number of medical technology and pharmaceutical patent grants by the WIPO is concerned, what sets the US, Germany, and Japan apart from the Philippines? A. Regulation B. Leadership C. Innovation D. Accessibility YL6:01.25a Drug Development 1 6. GLP (Good Laboratory Practice) primarily applies to which phase of studies? A. Clinical trials B. Pre-clinical studies C. Post-marketing surveillance D. Epidemiological studies 7. T/F: Metallo-β-Lactamase-1 is one of the dreaded enzymes because it intensifies the toxic effects of a wide variety of currently available drugs thus compromising their safety. 8. In developing leads into a product, this discipline or research body allows for the study of anatomic, physiologic, and biochemical processes A. Microbiology and ecology B. Chemistry and engineering C. Animal models D. Statisticians and data scientists 9. What continues to be the best and most established source of new molecules, as such, serves as the inspiration for the creation of new drugs? A. Nature B. Minerals C. Recombinant DNA Technology 10. PSURs frequency may be adjusted to a longer periodicity as determined by the HRA. Direct Healthcare Professional Communication is directed towards patients in order for them to report any substandard drugs released in the market. A. Only the first statement is true. B. Only the second statement is true C. Both statements are true. D. Both statements are false. ANSWER KEY 1B, 2D, 3F, 4B, 5C, 6B, 7F, 8C, 9A, 10A RATIONALE 1. B. Efficacy and potency of drugs. As the national medicines regulatory agency, FDA issues policies and guidelines observed by pharmaceutical companies in the Philippines, particularly: market authority, approval for licensing facilities, and registration of products. 2. D. Delay due to redundancies involved in drug development and regulatory approval is further minimized. Harmonization aims to minimize the delay due to redundancies of drug development and regulatory approval. Without ICH, a drug developed by the US would need to conduct a separate clinical trial for other countries. Given that clinical trials are very expensive and highly resource intensive, data generated from one regulatory agency can already be considered as supporting information for regulatory approval of another regulatory agency. ICH also ensures that clinical trial information is shared uniformly among the regulatory actors worldwide. 3. F. Not all targets identified by computer programs will yield something logical or directly observable. This is why Target Identification and Validation is an important step. 4. B. Only statement 2 is true. The idea of vaccination did not originate in Europe. This was already done by Mongols and Central Asians, Turks and Arabs even before Edward Jenner developed vaccines. 5. C. Innovation. In both medical technology and pharmaceuticals, the US, Germany, Japan remains innovative while the Philippines is surmised to be not innovative as it 9 belongs to the lowest category in new patents for medical technology and pharmaceuticals. 6. B. Pre-clinical studies. GLP (Good Laboratory Practice) applies to non-clinical laboratory studies in the pre-clinical studies phase, with emphasis on animal testing. 7. F. Metallo-β-Lactamase-1 is known to neutralize a wide variety of currently available antibiotics. 8. C. Animal models. Animals models such as mice, rates, rabbits, and monkeys are used to properly study anatomic, physiologic, and biochemical processes, and allow us to understand the disease in human models 9. A. Nature. Nature continues to be the best and most established source of new molecules. An example of how nature contributes to the creation of new drugs is the origin of Metformin. Metformin, a drug commonly used to control blood sugar, comes from goat’s rue, which is a plant. 10. A. Only the first statement is true. Drugs with stable safety profiles may have longer periodicity as compared to some drugs that do not have stable safety profiles. DHCP is directed towards healthcare professionals to actively report or recall drugs that do not meet safety standards. FREEDOM SPACE REFERENCES REQUIRED 💻 Chua, P.G.Y. (2023, August). Drug Development Part 1. [Asynchronous Lecture Video] ● 💻 Chua, P.G.Y. (2023, August). Drug Development Part 2. [Asynchronous Lecture Video] ● SUPPLEMENTARY ● 📄 ASMPH 2026. 01.23: Drug Development by Chua. P. G. Y., MD-MBA Concerns and Feedback form: http://bit.ly/YL6CFF2027 How’s My Transing? form: https://bit.ly/2027YL6HMT Mid-Semester Evaluation form: https://bit.ly/2027YL6MidSem End-of-Semester Evaluation form: https://bit.ly/2027YL6EndofSem YL6 TransMap: https://bit.ly/2027YL6TransMap YL6:01.25a Drug Development 1 10 APPENDIX Appendix A. Summary of the Discovery Process (ASMPH 2026, 01.23) YL6:01.25a Drug Development 1 11