Drug development is the process of bringing a new pharmaceutical drug to the market once a lead compound has been identified through the process of drug discovery. It includes preclinical research on microorganisms and animals, filing for regulatory status, such as via the United States Food and Drug Administration for an investigational new drug to initiate clinical trials on humans, and may include the step of obtaining regulatory approval with a new drug application to market the drug
Drug development is considered as a series of well defined steps, culminating, if successful, in market authorization, of the drug
Pharmacological Approach to Drug DiscoverySuhas Reddy C
For better understanding of students. This will give you a detailed explanation of Pharmacological approach. Contact me through comment section if you need any assistance in understating
Definition and scope of Pharmacoepidemiology ABUBAKRANSARI2
In these slides I shared the information of definition and scope of pharmacoepidemiology. Types of studies - cohort studies, cross-sectional studies etc.
The safety monitoring in a clinical trail accompanies by common practices in safety monitoring, communicating safety information among stakeholders in a clinical trail.
Pharmacological Approach to Drug DiscoverySuhas Reddy C
For better understanding of students. This will give you a detailed explanation of Pharmacological approach. Contact me through comment section if you need any assistance in understating
Definition and scope of Pharmacoepidemiology ABUBAKRANSARI2
In these slides I shared the information of definition and scope of pharmacoepidemiology. Types of studies - cohort studies, cross-sectional studies etc.
The safety monitoring in a clinical trail accompanies by common practices in safety monitoring, communicating safety information among stakeholders in a clinical trail.
Toxicological Approach to Drug DiscoverySuhas Reddy C
For better understanding of students. This will give you a detailed explanation of Toxicological approach. Contact me through comment section if you need any assistance in understating
For better understanding of students. This will give you a detailed explanation of IND APPLICATION. Contact me through comment section if you need any assistance in understating this topic.
Amendments in Schedule Y in 2013,2014 inserted three new rules, new appendix XII: compensation in case of injury or death during clinical trial, amendments in ICD and appendix V inform consent form format.
In these slides you can get the information of clinical trials which have four phase I,II,III, IV. before clinical trials, Pre-clinical studies should be completed.
The slide provides a basic understanding about Clinical Research process and the various Phases of Drug Discovery and Development. It also explains about the various trial designs and techniques in research such as blinding and randomization. It may be useful for giving a basic class for Fourth Year B.Pharm Students.
PHARMACOVIGILANCE TERMINOLOGIES ASKED IN INTERVIEWS-
For more information regarding PHARMACOVIGILANCE, CLINICAL RESEARCH, CLINICAL DATA MANAGEMENT & DRUG REGULATORY AFFAIRS kindly contact us on 9028839789
This presentation is a brief overview of ICH-GCP guidelines. Although ICH-GCP is a very vast topic, still this presentation will cover almost all the points. The reader will be able to discuss about the roles and responsibilities of various personnel in clinical trials.
In the slideshare i have discussed about principal of preclinical studies
various approaches towards preclinical studies
a route map of preclinical trials and its various methods
An overview of ICH-GCP guidelines of clinical trials.
Good clinical practice (GCP): a standard for the design , conduct, performance, monitoring, auditing, recording, analyses and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate and that the rights, integrity, and confidentiality of trial subjects are protected.
ICH-GCP is an International Conference on Harmonization Good Clinical Practice.
The guideline was developed with consideration of the current good clinical practices of the European union, Japan, and the United States, as well as those of Australia, Canada, the Nordic countries and the world health organization
Historically, drugs were discovered by identifying the active ingredient from traditional remedies or by serendipitous discovery, as with penicillin. More recently, chemical libraries of synthetic small molecules, natural products or extracts were screened in intact cells or whole organisms to identify substances that had a desirable therapeutic effect in a process known as classical pharmacology. After sequencing of the human genome allowed rapid cloning and synthesis of large quantities of purified proteins, it has become common practice to use high throughput screening of large compounds libraries against isolated biological targets which are hypothesized to be disease-modifying in a process known as reverse pharmacology. Hits from these screens are then tested in cells and then in animals for efficacy
Toxicological Approach to Drug DiscoverySuhas Reddy C
For better understanding of students. This will give you a detailed explanation of Toxicological approach. Contact me through comment section if you need any assistance in understating
For better understanding of students. This will give you a detailed explanation of IND APPLICATION. Contact me through comment section if you need any assistance in understating this topic.
Amendments in Schedule Y in 2013,2014 inserted three new rules, new appendix XII: compensation in case of injury or death during clinical trial, amendments in ICD and appendix V inform consent form format.
In these slides you can get the information of clinical trials which have four phase I,II,III, IV. before clinical trials, Pre-clinical studies should be completed.
The slide provides a basic understanding about Clinical Research process and the various Phases of Drug Discovery and Development. It also explains about the various trial designs and techniques in research such as blinding and randomization. It may be useful for giving a basic class for Fourth Year B.Pharm Students.
PHARMACOVIGILANCE TERMINOLOGIES ASKED IN INTERVIEWS-
For more information regarding PHARMACOVIGILANCE, CLINICAL RESEARCH, CLINICAL DATA MANAGEMENT & DRUG REGULATORY AFFAIRS kindly contact us on 9028839789
This presentation is a brief overview of ICH-GCP guidelines. Although ICH-GCP is a very vast topic, still this presentation will cover almost all the points. The reader will be able to discuss about the roles and responsibilities of various personnel in clinical trials.
In the slideshare i have discussed about principal of preclinical studies
various approaches towards preclinical studies
a route map of preclinical trials and its various methods
An overview of ICH-GCP guidelines of clinical trials.
Good clinical practice (GCP): a standard for the design , conduct, performance, monitoring, auditing, recording, analyses and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate and that the rights, integrity, and confidentiality of trial subjects are protected.
ICH-GCP is an International Conference on Harmonization Good Clinical Practice.
The guideline was developed with consideration of the current good clinical practices of the European union, Japan, and the United States, as well as those of Australia, Canada, the Nordic countries and the world health organization
Historically, drugs were discovered by identifying the active ingredient from traditional remedies or by serendipitous discovery, as with penicillin. More recently, chemical libraries of synthetic small molecules, natural products or extracts were screened in intact cells or whole organisms to identify substances that had a desirable therapeutic effect in a process known as classical pharmacology. After sequencing of the human genome allowed rapid cloning and synthesis of large quantities of purified proteins, it has become common practice to use high throughput screening of large compounds libraries against isolated biological targets which are hypothesized to be disease-modifying in a process known as reverse pharmacology. Hits from these screens are then tested in cells and then in animals for efficacy
Pre-discovery
Understand the disease
Target Identification
Choose a molecule to target with a drug
Target Validation
Test the target and confirm its role in the disease
Drug Discovery
Find a promising molecule (a “lead compound”)
that could become a drug
DRUG DISCOVERY & DEVELOPMENT PROCESS, it's a detail description about how drug is made available in market it's development and discovery of drug The Hole Study is given in This Topic.
A review on stages of drug development and alternative methods for animal stu...Frinto Francis
Various Stages of drug development, anaesthesia ,euthanasia, animals used for preclinical analysis, clinical trials, alternative methods for animal testing, blood withdrawal methods, ethical guidelines
Introduction to pre clinical screening of drugsKanthlal SK
Various Techniques and Methods for screening of new chemical entities in preclinical aspects (both invitro & invivo) for effective and safe clinical usage.
clinical and preclinical approaches to drug discovery.Here we mainly deals with preclinical approaches, ie. Pharmacological approach and toxicological approach
Drug development - Background informationXplore Health
This guide provides background information on the drug development process including the different phases and the ethical, legal and social aspects associated.
Genetic polymorphisms are variations in gene sequences that occur in at least 1% of the general population, resulting in multiple alleles or variants of a gene sequence.
The most commonly occurring form of genetic variability is the single nucleotide polymorphism (SNP, often called “snip”)
Population pharmacokinetics is the study of the sources and correlates of variability in drug concentrations among individuals who are the target patient population receiving clinically relevant doses of a drug of interest
Clinical pharmacokinetics is the discipline that applies pharmacokinetic concepts and principles in humans in order to design individualized dosage regimens which optimize the therapeutic response of a medication while minimizing the chance of an adverse drug reaction.
Cardiac cycle is defined as the succession of coordinated events taking place in the heart during each beat. Each heart beat consists of two major periods called systole and diastole.
Although some lymphocytes have a lifetime measured in years, most formed elements of the blood last only hours, days, or weeks, and must be replaced continually.
Negative feedback systems regulate the total number of RBCs and platelets in circulation, and their numbers normally remain steady.
The abundance of the different types of WBCs, however, varies in response to challenges by invading pathogens and other foreign antigens.
The heart has four chambers. The two superior receiving chambers are the atria (= entry halls or chambers), and the two inferior pumping chambers are the ventricles (= little bellies).
On the anterior surface of each atrium is a wrinkled pouchlike structure called an auricle
Desmopressin
Lypressin
Terlipressin
Felypressin
Argipressin
ornipressin
Desmopressin: It is a selective V2-receptor agonist and is more potent than vasopressin as an antidiuretic. It has negligible vasoconstrictor action. It is administered by oral, nasal and parenteral routes. Lypressin: It acts on both V1- and V2-receptors. It is less potent but longer acting than vasopressin. It is administered parenterally. Terlipressin: It is a prodrug of vasopressin with selective V1 action. It is administered intravenously. Felypressin: It is a synthetic analogue of vasopressin. It is mainly used for its vasoconstrictor (V1 ) action along with local anaesthetics to prolong the duration of action. Felypressin should be avoided in pregnancy because of its oxytocic (uterine stimulant) activity.
Management of Peripheral Neuropathy and Cardiovascular Effects in Vitamin B1...PARUL UNIVERSITY
Peripheral nerves are susceptible to damage by a wide array of toxins, medications, and vitamin
deficiencies. Vitamin B12 (VB12) deficiency neuropathy is a rare debilitating disease that affects
mostly the elderly. It is important to consider these etiologies when approaching patients with a variety
of neuropathic presentations in this review were have included most relevant and latest information on
mechanisms causing Peripheral neuropathy in VB12 deficiency. We also have included cardiovascular
disorders and their management. Hyperhomocysteinemia has been implicated in endothelial
dysfunction and cardiovascular disease. The association of homocysteine (Hcy) and VB12 with
cardiovascular risk factors in patients with coronary artery disease (CAD) has also been studied
Moyamoya disease (MMD) is a rare and unique cerebrovascular disease. The term “moyamoya” is Japanese and refers to a hazy puff of smoke or cloud. In people with moyamoya disease, this is how the blood vessels appear in the angiogram. MMD is characterized by the progressive stenosis of the distal internal carotid artery (ICA) resulting in a hazy network of basal collaterals called moyamoya vessels. This may be a consequence of Mutations in a few genes. In addition, MMD is also associated with many genetically transmitted disorders, including neurofibromatosis, Down syndrome, Sickle cell anemia, and Collagen vascular disease. It follows bimodal age distribution. Younger populations present with ischaemic symptoms, whereas adults show hemorrhagic symptoms The exact cause remains unknown. Immune, genetic and other factors contribute to this disease. It follows complex pathophysiology resulting in neovascularization as a compensatory mechanism. Diagnosis is based on cerebral angiography using the DSA scale. Treatment involves managing symptoms with medicine or surgery, improving blood flow to the brain, and controlling seizures. Revascularization helps to rebuild the blood supply to the underside of the brain.
A case report on Rheumatoid Arthritis with sickle cell traitPARUL UNIVERSITY
A female patient aged 6 years, a suspected case of sickle cell trait (SCT) having symptoms of Rheumatoid arthritis (RA),
while evaluating joint complaints in adult sickle cell disease (SCD) patients, a number of sickle cell-based entities come
to mind such as avascular necrosis, osteomyelitis, bone infarcts, and septic arthritis. RA is a chronic systemic
inflammatory disease, many reports highlighted the occurrence of RA in SCD presenting as diagnostic challenges for
cases with chronic inflammatory arthritis, SCT also have appeared to persist in some populations at a perplexingly high
rate given the degree of early mortality of homozygosity of SCD, our case report showed that not only SCD but if a patient
has SCT they can develop RA as complication. Our case report concludes that during the evaluation of a SCT patient who
presents with chronic synovitis, one should strongly consider the possibility of coexistence of RA and SCT.
The appendicular skeleton consists of the
shoulder girdle with the upper limbs and the
pelvic girdle with the lower limbs
Shoulder girdle and upper limb:
Each shoulder girdle consists of:
•1 clavicle
•1 scapula.
Each upper limb consists of the following bones:
1 humerus, 1 radius, 1 ulna, 8 carpal bones, 5 metacarpal bones and 14 phalanges.
Histamine is a biogenic amine present in many animal and plant tissues that function as neurotransmitters and are also found in non-neural tissues, have complex physiologic and pathologic effects through multiple receptor subtypes, and are often released locally.
It is also present in venoms and stinging secretions. It is synthesized by decarboxylation of the amino acid, histidine. Histamine is mainly present in storage granules of mast cells in tissues like skin, lungs, liver, gastric mucosa, placenta, etc. It is one of the mediators involved in inflammatory and hypersensitivity reactions.
Anabolic steroids promote protein synthesis and increase muscle mass, resulting in weight gain.
Testosterone is secreted by the testis and is the main androgen in the plasma of men. In women, testosterone (in small amounts) is secreted by the ovary and adrenal glands. Many of the androgens are modified forms of testosterone
Kinetics: Absorbed orally and from of injection site and undergoes rapid first pass metabolism and quick metabolism respectively. In order to retard the rate of absorption, testosterone esters in oil are used which are less polar than the free steroid.
DKA
HHS
CASE DISCUSSION
DIABETES COMPLICATION
Hyperglycaemia is the main cause leading to dehydration due to osmotic diuresis which, if severe, results in hyperosmolarity. In HHS, unlike diabetic ketoacidosis, there is no significant ketone production and therefore no severe acidosis.
Hyperosmolarity may increase blood viscosity and the risk of thromboembolism. Factors precipitating HHS are infection, myocardial infarction, poor adherence with medication regimens or medicines which cause diuresis or impair glucose tolerance, for example, glucocorticoids.
A study on the pharmacological management of mineral bone disease in chronick...PARUL UNIVERSITY
In patients with chronic kidney disease (CKD), along with progression of CKD,
abnormalities of mineral and bone metabolism develop, which result in altered serum levels of minerals
such as calcium and phosphorus, as well as abnormalities in parathyroid hormone (PTH) or vitamin D
metabolism. Chronic Kidney Disease-Mineral Bone Disease (CKD-MBD) is a serious burden because of
increased cardiovascular mortality thus making therapeutic improvements essential in CKD-MBD. The
present study was aimed at evaluation of pharmacological management of CKD-MBD.
Methods:A retrospective study including 180 patients divided into two groups of 90 each (diabetes
mellitus and non-Diabetes) was performed in the Department of Nephrology, SVIMS, Tirupati. Patients
who were on follow up for at least 3 years (2015-2017) were considered, serum parameters were measured at every six months with a total of 6 visits. First visit was taken as baseline and sixth visit as
conclusion.
Results:The disease incidence of CKD-MBD is more common in male patients i.e. 67.8%. Serum calcium
levels were significantly increased and eGFR was significantly decreased in all patients with CKD at
conclusion compared to baseline.Further, Serum calcium levels were significantly increased at conclusion
in CKD patients without DM and eGFR was significantly decreased at conclusion compared to baseline
in CKD patients with DM. The proportion of untreated patients is high for all the drugs except vitamin D
analogues in both subgroups of CKD patients.
Conclusion:Pharmacological intervention in CKD patients helps in the effective management of mineral
bone disease by maintaining serum calcium, phosphate and calcium phosphorous product status.
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
Couples presenting to the infertility clinic- Do they really have infertility...
Clinical research unit 1
1. DRUG DEVELOPMENT PROCESS
D R . S P S R I N I V A S N A Y A K
A S S I S T A N T P R O F E S S O R , P I P R
P A R U L U N I V E R S I T Y .
2. DEFINITION
Drug development is the process of bringing a new pharmaceutical drug to
the market once a lead compound has been identified through the process
of drug discovery. It includes preclinical research on microorganisms and
animals, filing for regulatory status, such as via the United States Food and
Drug Administration for an investigational new drug to initiate clinical trials
on humans, and may include the step of obtaining regulatory approval with
a new drug application to market the drug
Drug development is considered as a series of well defined steps,
culminating, if successful, in market authorization, of the drug
D R S P N A Y A K - P A R U L U N I V E R S I T Y 2
3. D R S P N A Y A K - P A R U L U N I V E R S I T Y 3
4. Various Steps Involved in Drug Development
Process
New drug discovery
Preclinical testing
Investigational New Drug Application (IND)
Clinical Trials (phase I,II,II trails)
New Drug Application (NDA)
Post Marketing Surveillance / phase IV clinical trials
D R S P N A Y A K - P A R U L U N I V E R S I T Y 4
5. New Drug Discovery
Definition : Drug discovery is the process of identifying compounds that
have the
potential to become useful new therapies
Common ways of developing new drugs
1. From natural products e.g. plants and animals
2. changing the chemical structure of existing molecules
3. Studying disease process
4. Using computers to design new drugs
5. Serendipity : observation by chance e.g. penicillin
D R S P N A Y A K - P A R U L U N I V E R S I T Y 5
6. NEW DRUG DISCOVERY (CONT.)
The first phase, target selection, involves choosing a disease to treat and
then developing a model for that disease AND target validation
The second phase, drug selection(Lead identification), is a process that
involves finding a drug or group of drugs that work within that model
system and Lead optimization
The third phase, product development, is a process that involves
discovering a biological target such as a particular enzyme, receptor or
ion channel that the scientific team believes may be linked to a
pathologic process D R S P N A Y A K - P A R U L U N I V E R S I T Y 6
7. in
1.dafajhska 11. 2
SCHGA
a
1. Identification
and validation
of biological
target
2. Development of
assay and
screening of large
compound
collections
3. Optimizing hit
compounds to
improve efficacy,
safety, stability etc.
Robotic high
throughput screening
Safety,
pharmacokinetics and
pharmaceutics
Intellectual
property
Application of
Genomics/
Bioinformatics
Compound
collection
Combinatoria
l
biosynthesis/
chemistry
Inputs from the
global
market/busines
s
4. Selection of final
candidate(s)
Molecular
modelling
Figure : The Drug Discovery
Process
D R S P N A Y A K - P A R U L U N I V E R S I T Y 7
8. Current Methods Used In Drug Discovery Process
This includes -
1. Identification of novel pathways that are associated with disease,
selection of target in the pathway and development of screens
2. Screening large compounds and natural compounds (from plants,
animal products or microorganisms) for the desired activity
3. Molecular modelling using powerful software graphics and stimulation
programs to generate 3D structures of target molecules and model the
affinity of different molecules at these targets
D R S P N A Y A K - P A R U L U N I V E R S I T Y 8
9. CURRENT METHODS USED IN DRUG DISCOVERY PROCESS
4. Targeted synthesis, i,e. the creation of original molecules with
biological activities that target particular stages of disease process.
Researchers design and synthesize molecules that bind to particular
locus on a target
5. Combinatorial chemistry consists of systematically modifying and
existing compound chemically to act on a selected target. Screening
of multiple compounds sometimes produce clue about how structural
modification alters the action of a compound . Subsequent chemical
modification of a lead compound can result in a compound with
enhanced properties, such as improved absorption, enhanced safety,
D R S P N A Y A K - P A R U L U N I V E R S I T Y 9
10. New technologies that are pivotal to the drug discovery and
development
Medical genetics : genetic linkage studies are used to sift through the
human genome to link genes with particular disease, while genetic
association studies are used to look for gene sequences in unselected
individuals to determine whether they are more common in one disease than
another
Combinatorial biosynthesis : it is a technique for modelling and building
libraries of chemical compounds for consideration as drug candidates
• Within these libraries, information system are being designed to link
chemical structures with various biological activities
D R S P N A Y A K - P A R U L U N I V E R S I T Y 10
11. NEW TECHNOLOGIES THAT ARE PIVOTAL TO THE DRUG DISCOVERY
AND DEVELOPMENT (CONT.)
Robotic high-throughput screening : using miniaturization and fully
automated robotic technology, compounds generated from
combinatorial chemistry are tested in primary activity screens,
identifying lead compound for further biological testing and chemical
optimization
Bioinformatics : information systems developed for analysis of
biological, particularly genomic data. Bioinformatics is used for gene
identification and mapping, comparing sequence data in search of
similarities, linking genes with their associated proteins and biological
functions. Ultimately , it is used to identify and validate new targets and
D R S P N A Y A K - P A R U L U N I V E R S I T Y 11
12. Preclinical Testing
Preclinical tests are performed in laboratory, using a wide array of chemical
and biochemical assays, cell culture and animal models. The pharmacological
activity of every new compound is carefully analyzed
Preclinical testing involves :
• Pharmacology testing
• Toxicology testing
• Animal Pharmacokinetics testing
D R S P N A Y A K - P A R U L U N I V E R S I T Y 12
13. PHARMACOLOGY TESTING
These are the studies to explore the pharmacological activity and therapeutic
potential of compounds. These tests involve the use of animals, isolated cell
cultures and tissues, enzymes and cloned receptor sites as well as computer
models
If the results of the test suggest potential beneficial activity, related compounds
(each a unique structural modification of the original) are tested to see which
version of the molecule produces the highest level of pharmacological activity
and demonstrates the most therapeutic promise, with the smallest number of
potentially harmful biological properties
D R S P N A Y A K - P A R U L U N I V E R S I T Y 13
14. PHARMACOLOGY TESTING (CONT.)
Animal pharmacology studies allow the effects of the lead compound on
the disease process (pharmacodynamics) to be corelated with the
concentration of compound needed to achieve these effects
(pharmacokinetics)
Animal pharmacology testing is performed in animal models of human
disease. Animal model of human disease may occur :
1. Naturally i.e, squirrel monkeys develop dementia in old age that is
behaviorally and histologically similar to Alzheimer's disease in humans
D R S P N A Y A K - P A R U L U N I V E R S I T Y 14
15. PHARMACOLOGY TESTING (CONT.)
2. By introduction of genetic defect in germ cells of an animal strain so
that its reproduction produces off springs with the disease of interest. For
example, introducing a mutation that prevents the serotonin 2C receptor
from functioning results in animals that exhibit anxiety
3. Using toxins that selectively destroy a particular type of cells. Eg:
administrating the neurotoxin MPTP selectively destroys dopaminergic
neurons in the brain, producing Parkinson's like disease state
D R S P N A Y A K - P A R U L U N I V E R S I T Y 15
16. Toxicological testing
• Toxicological studies will be carried out in both in vitro and on animal species
known to have drug metabolism and disposition parameters (the fate of the
drug in the body) resembling those in humans, although the pharmaceutical
industry is always striving to replace animal experiments with meaningful In
vitro studies (such as the Ames test)
• Toxicology and safety testing determine the potential risk a compound poses to
man and the environment
• Generally, two or more species ( one rodent, one non-rodent) are tested
because a drug may effect one species differently from another
D R S P N A Y A K - P A R U L U N I V E R S I T Y 16
17. Toxicity studies are done to calculate :
Maximum tolerated dose
Gross pathology to indicate target organs
Satisfactory therapeutic with regard to animal efficacy studies
They are conducted to :
Select or reject lead candidate
General indication of suitability
Dose selection and guidance to clinician
Toxicological testing (cont.)
D R S P N A Y A K - P A R U L U N I V E R S I T Y 17
18. Types of Toxicology Investigations
Toxicity Studies Required for Complete Preclinical Development of the Drug
Types Duration of the study
Acute toxicity • 2 week studies in 3-4 species to determine
maximum tolerated dose
Sub- acute toxicity • 6 month studies in 2 species
Chronic toxicity • Up to 12 month studies in rats and a non rodent
to determine If adverse effects occur with
repeated daily dosing
• Oncology studies- at least 18 months in mice
- 2 years in rat
D R S P N A Y A K - P A R U L U N I V E R S I T Y 18
19. Types Duration of the study
Reproductive Up to 9 month studies in 2 species to determine
effects of drug on fertility and reproduction and
expose any teratogenic effects
Mutagenic 18-24 month in vitro and in vivo studies
Types of Toxicology Investigations cont.
Toxicity Studies Required for Complete Preclinical Development of the Drug
D R S P N A Y A K - P A R U L U N I V E R S I T Y 19
20. If the results of these toxicity studies indicate that the range between biological
activity and toxicity is acceptable, the company will apply to the relevant
regulatory body for permission to continue development (example: if the
regulatory body is the FDA, an Investigational New Drug (IND) application can
be filed at this stage)
Acceptable Toxicity
Extensive toxicity studies ensure that drugs causing serious toxicity do not
reach the market- unless of course, the agent concerned has a potentially life
saving role in treating a disease and where no other more suitable drugs are
available
Toxicological testing
(cont.)
D R S P N A Y A K - P A R U L U N I V E R S I T Y 20
21. At present, HIV infection represents such a serious threat to life it is considered
acceptable to use drugs to treat it which are rather toxic to human body
Animal Pharmacokinetics testing
Pharmacokinetic studies are used to measure how much of a drug is absorbed
into the blood (drug absorption), how it is broken down chemically in the body, the
toxicity of the drug, its breakdown products (metabolites), and how quickly the
drug and its metabolites are excreted from the body (excretion)
If the compound is successful and continues its progression through the
development process, the studies will be repeated in humans
Toxicological testing
(cont.)
D R S P N A Y A K - P A R U L U N I V E R S I T Y 21
22. Investigational New Drug Application (IND)
After completing preclinical testing, the company files an IND with FDA or
DCGI in India to begin to test the drug in human
INDA (Investigational New Drug Application) is the means through which
sponsor (manufacturer or potential marketer) obtain a legal status to call its
new investigational molecule as new drug
D R S P N A Y A K - P A R U L U N I V E R S I T Y 22
23. INVESTIGATIONAL NEW DRUG APPLICATION (IND) (CONT.)
The IND is not an application for marketing approval
A sponsor will probably want to ship the investigational drug to clinical
investigators in many states, it must seek an exemption from the legal
requirement
The IND is the means through which the sponsor technically obtains this
exemption from the FDA
However, its main purpose is to detail the data that provide documentation to
proceed with certain human trails with the drug
The IND becomes effective if FDA does not disapprove it within 30 days
D R S P N A Y A K - P A R U L U N I V E R S I T Y 23
24. INVESTIGATIONAL NEW DRUG (CONT.)
Drug developers, or sponsors, must submit an Investigational New Drug
(IND) application to FDA before beginning clinical research
In the IND application, developers must include:
Animal study data and toxicity (side effects that cause great harm) data
Manufacturing information
Clinical protocols (study plans) for studies to be conducted
Data from any prior human research
Information about the investigator
D R S P N A Y A K - P A R U L U N I V E R S I T Y 24
25. INVESTIGATIONAL NEW DRUG (CONT.)
Asking for FDA Assistance
Drug developers are free to ask for help from FDA at any point in the drug
development process, including:
Pre-IND application, to review FDA guidance documents and get answers
to questions that may help enhance their research
After Phase 2, to obtain guidance on the design of large Phase 3 studies
Any time during the process, to obtain an assessment of the IND
application
D R S P N A Y A K - P A R U L U N I V E R S I T Y 25
26. INVESTIGATIONAL NEW DRUG (CONT.)
Even though FDA offers extensive technical assistance, drug
developers are not required to take FDA’s suggestions
As long as clinical trials are thoughtfully designed, reflect what
developers know about a product, safeguard participants, and
otherwise meet Federal standards, FDA allows wide latitude in
clinical trial design
D R S P N A Y A K - P A R U L U N I V E R S I T Y 26
27. INVESTIGATIONAL NEW DRUG (CONT.)
FDA IND Review Team
The review team consists of a group of specialists in different scientific
fields. Each member has different responsibilities
Project Manager: Coordinates the team’s activities throughout the review
process, and is the primary contact for the sponsor
Medical Officer: Reviews all clinical study information and data before,
during, and after the trial is complete
D R S P N A Y A K - P A R U L U N I V E R S I T Y 27
28. INVESTIGATIONAL NEW DRUG (CONT.)
Statistician: Interprets clinical trial designs and data, and works closely
with the medical officer to evaluate protocols and safety and efficacy
data
Pharmacologist: Reviews preclinical studies
Pharmakineticist: Focuses on the drug’s absorption, distribution,
metabolism, and excretion processes. Interprets blood-level data at
different time intervals from clinical trials, as a way to assess drug
dosages and administration schedules
D R S P N A Y A K - P A R U L U N I V E R S I T Y 28
29. INVESTIGATIONAL NEW DRUG (CONT.)
Chemist: Evaluates a drug’s chemical compounds. Analyzes how a drug
was made and its stability, quality control, continuity, the presence of
impurities
Microbiologist: Reviews the data submitted, if the product is an
antimicrobial product, to assess response across different classes of
microbes
D R S P N A Y A K - P A R U L U N I V E R S I T Y 29
30. INVESTIGATIONAL NEW DRUG (CONT.)
The FDA review team has 30 days to review the original IND submission.
The process protects volunteers who participate in clinical trials from
unreasonable and significant risk in clinical trials
FDA responds to IND applications in one of two ways: Approval to begin
clinical trials and clinical hold to delay or stop the investigation. FDA
can place a clinical hold for specific reasons, including:
Participants are exposed to unreasonable or significant risk
Investigators are not qualified
Materials for the volunteer participants are misleading
The IND application does not include enough information about the trial’s risks
D R S P N A Y A K - P A R U L U N I V E R S I T Y 30
31. If FDA is satisfied that the trial meets Federal standards, the applicant is
allowed to proceed with the proposed study
The developer is responsible for informing the review team about new
protocols, as well as serious side effects seen during the trial. After the
trial ends, researchers must submit study reports
This process continues until the developer decides to end clinical trials or
files a marketing application. Before filing a marketing application, a
developer must have adequate data from two large, controlled clinical
trials D R S P N A Y A K - P A R U L U N I V E R S I T Y 31
Investigational New Drug (cont.)
32. Clinical trials/ Clinical Development of Drug
The clinical development plan
The safety and toxicity data generated from preclinical studies enables the drug
company to safely initiate clinical trials
Clinical trials on patients in different countries are approved and monitored by
different regulatory agencies like:
1. In India, Drug Controller General of India (DCGI) office under Central Drug
Standard Control Organization (CDSCO)
D R S P N A Y A K - P A R U L U N I V E R S I T Y 32
33. CLINICAL TRIALS/ CLINICAL DEVELOPMENT OF DRUG
(CONT.)
2. In UK, Medicines and Healthcare products Regulatory Agency
(MHRA) , advised by the Committee on Safety of Medicines (CSM)
3. In USA , Food and Drug Administration (FDA)
D R S P N A Y A K - P A R U L U N I V E R S I T Y 33
34. Phases of clinical trials
• Clinical research is done in four phases (I,II,III and IV), each designed to
address different questions
• The knowledge gained from one phase is assessed before progressing to
the next phase
• However, research in a particular phase may continue after the drug has
progressed to further stages of development
D R S P N A Y A K - P A R U L U N I V E R S I T Y 34
35. PHASES OF CLINICAL TRIALS (CONT.)
Based on the data gathered from the preclinical trials/ animal
testing, the sponsor has some estimation of:
The drug’s therapeutic effect and dose levels
Toxicity profile and dose levels
This information is used in the design of phase I clinical trials
D R S P N A Y A K - P A R U L U N I V E R S I T Y 35
36. PHASE 1
The first question in drug research is to find out the safety of drug in
humans. Phase I studies, sometimes called as “first in man”, starts to
answer this question by testing the investigational product in healthy
volunteers
If the drug has the potential for toxic adverse events, it may be given only
to subjects with the targeted condition to reduce risks to healthy
subjects (example: anticancer drugs are never tested in healthy
volunteers)
D R S P N A Y A K - P A R U L U N I V E R S I T Y 36
37. PHASE 1 (CONT.)
The main purpose of the initial phase I studies is to establish a safe
dosage range
During the phase I studies, sufficient information about the drug’s
pharmacokinetics (ADME) and pharmacological effects should be
obtained to permit the design of well-controlled, scientifically valid,
phase II studies
Phase 1 studies also evaluate drug metabolism, structure activity
relationships, and the mechanism of action in humans
D R S P N A Y A K - P A R U L U N I V E R S I T Y 37
38. PHASE 1 (CONT.)
These are generally conducted on 20-80 healthy human volunteers and typically
lasts for 3-6 months
Initially, a single small dose is administered to each volunteer in a hospital –
type setting ( perhaps a purpose- built unit within/outside the drug company’s
premises) so that the effects of the drug can be closely monitored
In phase I studies, regulatory bodies (FDA) can impose a clinical hold ( i,e,
prohibit the study from proceeding or stop a trial that has started) for reasons
of safety, or because of a sponsor’s failure to accurately disclose the risk of
study to investigators
D R S P N A Y A K - P A R U L U N I V E R S I T Y 38
39. PHASE 1 (CONT.)
Phase I trials address:
How rapidly the drug is absorbed ?
Where is the drug distributed in the body?
Which organs or organ systems are involved in metabolism of the
drug?
How quickly is the drug eliminated from the body?
Only about 70% of experimental drugs passes Phase I clinical trials
D R S P N A Y A K - P A R U L U N I V E R S I T Y 39
40. PHASE 2
Phase I clinical trials gives valuable information about any adverse reactions and
fate of the drug in the healthy human body, these parameters may be different in
patients suffering from the disease which the drug under test is designed to treat
For example: some antibiotics like benzylpenicillin only penetrate into the CSF if
the meninges are inflamed whereas penetration is poor in healthy individuals
Phase II clinical trials are conducted on patients. The main question asked by
Phase II studies is: “ what is the most effective dosage range and is the drug safe
within that range?”
D R S P N A Y A K - P A R U L U N I V E R S I T Y 40
41. PHASE 2 (CONT.)
Phase II studies enroll small number of subjects, typically 100 to
300 and the trial may last from 6 months to 2 years
The primary aims of Phase II clinical trials are to establish clinical
efficacy, determine the incidence of ADRs, define the optimum
therapeutic dosage and provide detailed pharmacokinetic and
pharmacological data to substantiate the adequate trial of the
drug
D R S P N A Y A K - P A R U L U N I V E R S I T Y 41
42. PHASE 2 (CONT.)
Trials on patients may be conducted in an open (non-blind) manner, where the
patients know whether they are receiving the drug or whether they are
receiving a placebo (an inactive material serving as a negative control) and
also as blind trials
In single blind trials, only the patients do not know whether they are receiving the
drug or the placebo
In double blind trials, both the patient and the clinical investigators do not know
which agent the patient is receiving
D R S P N A Y A K - P A R U L U N I V E R S I T Y 42
43. PHASE 2 (CONT.)
Phase II trial address:
What is the minimum effective dose?
What is the maximum tolerated effective dose?
Is the drug effective in mild, moderate, and severe cases of the disease or
condition?
Is the drug effective for all expected indications?
Only about 35% of experimental drugs passes Phase II clinical trials
D R S P N A Y A K - P A R U L U N I V E R S I T Y 43
44. PHASE 3
Phase III studies are expanded controlled and uncontrolled trials
They are performed after preliminary evidence suggesting effectiveness
of drug has been obtained in Phase II, and are intended to gather the
additional information about effectiveness and safety that is needed to
evaluate the overall benefit- risk relationship of the drug
Phase III clinical trials may involve several hundreds to several thousand
patients and lasts for 1-5 years
D R S P N A Y A K - P A R U L U N I V E R S I T Y 44
45. PHASE 3 (CONT.)
The main aim of this phase is to verify the drug’s effectiveness and any ADRs in
a large group of patients over a longer period of exposure, to establish the
safety and efficacy of the drug
Very often Phase III trials involve different patient sub- groups, such as children,
the elderly, and perhaps those with impairments in kidney and liver function
Once the Phase III has been completed satisfactorily, the drug company is in a
position to apply the marketing application to the regulatory authorities to market
the drug
D R S P N A Y A K - P A R U L U N I V E R S I T Y 45
46. PHASE 3 (CONT.)
Phase III trials address:
Overall risk-benefit relationship
Adverse reactions in large group of patients over a longer period of
exposure
The ideal dosage regimen
Is the drug allowed to be marketed?
Only about 25% of experimental drugs passes Phase III clinical trials
D R S P N A Y A K - P A R U L U N I V E R S I T Y 46
47. New Drug Application (NDA)
• Following the completion of all three phases of clinical trials, the company
analyzes all of the data and files an New Drug Application (NDA) with FDA, if
the data successfully demonstrate safety and effectiveness
• The NDA must contain all of the scientific information that the company has
gathered
• NDAs typically run 100,000 pages or more. By law, FDA is allowed six
months to review an NDA
D R S P N A Y A K - P A R U L U N I V E R S I T Y 47
48. NEW DRUG APPLICATION (NDA) (CONT.)
In almost all cases, the period between the first submission of an NDA and
final FDA approval exceeds that limit; the average NDA review time for
new molecular entities approved in 1992 was 29.9 months
Submitting an Application
Submission of a Marketing Authorization Application (i.e NDA to FDA) to a
Regulatory Authority requires extensive documentation since it covers
every aspect of the product development from its initial chemical
characterization to its claimed efficacy
D R S P N A Y A K - P A R U L U N I V E R S I T Y 48
49. NEW DRUG APPLICATION (NDA) (CONT.)
The main section of a typical new drug application to the regulatory
authorities are:
1. Dossier summary
Administrative data; summary of the product characteristics; expert
reports on chemical; pharmaceutical and clinical documentation
2. Chemical, Pharmaceutical and Biological Documentation Composition;
method of preparation; control of starting materials; control tests on
intermediate products; control tests on the finished product; stability
D R S P N A Y A K - P A R U L U N I V E R S I T Y 49
50. NEW DRUG APPLICATION (NDA) (CONT.)
3. Pharmaco-Toxicological Documentation
Single and repeated dose toxicity; reproductive studies; mutagenic potential;
oncogenic/carcinogenic potential; pharmacodynamics; pharmacokinetics; local
tolerance
4. Clinical Documentation
Clinical pharmacology; clinical experience
5. Special Particulars
Dosage form; samples; manufacturers authorization; marketing authorization
D R S P N A Y A K - P A R U L U N I V E R S I T Y 50
51. NEW DUG APPLICATION (NDA) (CONT.)
Successful Application
Assuming that the Regulatory Authority grants a product license, the
product can be marketed in the relevant countries
Product Registration
To be marketed, medicines needs to receive approval from the appropriate
Regulatory Authorities
D R S P N A Y A K - P A R U L U N I V E R S I T Y 51
52. NEW DRUG APPLICATION (NDA) (CONT.)
For example: In India, DCGI is the final authority for approval of a new
drug for marketing
FDA is the final authority for approval of a new drug for marketing in
United States
Only 1 in every 3 drugs which reach the market recoups its development
costs
Product manufacture
Considerations about the large-scale manufacture of the drug molecules
and the dosage forms takes place at an early stage in the development
process
D R S P N A Y A K - P A R U L U N I V E R S I T Y 52
53. NEW DRUG APPLICATION (NDA) (CONT.)
The full- scale production of the drug involves a large number of people of
different scientific disciplines (such as chemists, process engineers, plant
designers etc)
The life of a patent for a new drug is 20 years
If it takes 10-14 years to develop the product and clinically test it before
permission is granted by the regulatory authorities to market it, the drug
company will wish to manufacture it as soon as it can to claim as much of the
patent life as possible
Once the patent has expired, other manufacturers can produce the product
(called a Generic version) and sell it at lower cost
D R S P N A Y A K - P A R U L U N I V E R S I T Y 53
54. POST MARKETING SURVEILLANCE / PHASE IV CLINICAL
TRIALS
Sometimes adverse drug reactions only come into light after the drug
has been in the market for a while and has been used by very large
number of patients. Phase IV Clinical Trials identifies such problems
Withdrawal of drug from the market is not an uncommon occurrence,
one notorious case in the 1960’s involved the drug Thalidomide
Phase IV Clinical Trials are done after a drug has been shown to work
and has been granted a license
D R S P N A Y A K - P A R U L U N I V E R S I T Y 54
55. POST MARKETING SURVEILLANCE / PHASE IV CLINICAL
TRIALS
(CONT.)
Phase IV clinical trials address :
More about the side effects and safety of the drug?
What the long term risks and benefits of the drug are?
How well the drug works when it’s used more widely than in clinical
trials?
D R S P N A Y A K - P A R U L U N I V E R S I T Y 55
56. Dosage forms
Pre- formulation:
• Before a drug can be formulated into a medicine (a dosage form) which
can be administered to a patient, something must be known about its
physio-chemical properties and behavior (e.g. its solubility, its crystal
structure)
• These will dictate, to a certain extent, the dosage form(s) in which the
medicine will be marketed and the dosage form(s) which can be used
during drug development investigations
• Such data are gathered in pre-formulation studies and these play an
important part in anticipating formulation problems later on
D R S P N A Y A K - P A R U L U N I V E R S I T Y 56
57. DOSAGE FORMS (CONT.)
For example: aspirin can be satisfactorily formulated as a tablet but is too
unstable in aqueous solution to be formulated as a liquid dosage form
Although soluble or dispersible aspirin tablets are designed to be added to
water, this is only satisfactory if the resulting solution or suspension is taken
immediately
As a second example, benzylpenicillin is inactivated by gastric acid so is
available as an injection, rather than as a preparation which can be taken
orally
It is manufactured as the sodium or potassium salt to make it dissolve readily in
water prior to injection
Its packed in vials as a powder because it is susceptible to hydrolysis if stored
D R S P N A Y A K - P A R U L U N I V E R S I T Y 57
58. Drug characterization
Spectroscopy To produce a simple method for analysis of the drug
Solubility For identifying the best salt to develop and for producing
liquid dosage forms
Melting point Which reflects, for example, crystalline solubility
Assay development Necessary for drug stability studies and perhaps
employing thin layer or high pressure liquid
chromatography
D R S P N A Y A K - P A R U L U N I V E R S I T Y 58
59. Stability In solution and in the solid state
Microscopy To determine crystal morphology and particle size
Powder flow and
compression
properties
Necessary data for capsule and tablet formation
Excipient
compatibility
To ensure that dosage forms perform correctly
Drug characterization (cont.)
D R S P N A Y A K - P A R U L U N I V E R S I T Y 59
60. Types of Drug dosage forms
Tablets and capsules Convenient and commonest dosage forms but likely to
be no good if the drug cannot be absorbed in the
alimentary tract of if the patient ( for e.g. child) cannot
swallow them
Injections and
infusions
Rapid action but impractical for treating chronic (long
term) illnesses
Pessaries and
suppositories
Can deliver the drug to local area where required but
have limited general use
Solutions,
suspensions and
elixirs
Useful for children and elders but bulky and less useful
if the drug is unpalatable or unstable in the presence of
water D R S P N A Y A K - P A R U L U N I V E R S I T Y 60
61. Ointments, creams
and paints
Use in restricted to topical application
Aerosols and dry
powder inhalations
Good for drugs required in the large but can be
difficult to administer the dose correctly
Transdermal
patches
Convenient if the dose needs to be released over a
long period ( for example: hormone replacement
therapy) but can cause irritation
Types of Drug dosage forms (cont.)
D R S P N A Y A K - P A R U L U N I V E R S I T Y 61
62. EXAMPLES FOR DOSAGE FORMS
Therapeutic considerations play an important role in deciding the dosage
form to formulate
Some examples include
A tablet is not suitable dosage form if the drug cannot be absorbed in the
alimentary tract – unless, of course, it is required to treat an ailment in
the tract itself ( such as gut infection)
Instead of a tablet, an injection might be suitable alternative
D R S P N A Y A K - P A R U L U N I V E R S I T Y 62
63. EXAMPLES FOR DOSAGE FORMS CONT.
Even if the drug can be absorbed in the alimentary tract (example:
intestine), a simple tablet will still be unsatisfactory if the drug is
destroyed by the stomach acid
In such a case the tablet might be enteric coated to prevent drug
destruction while the tablet is passing through the stomach
By the time the tablet reaches the intestine the coating has dissolved
liberating the drug for absorption through the intestinal wall
D R S P N A Y A K - P A R U L U N I V E R S I T Y 63
64. Drugs which need to act immediately (example: bronchodilator drugs for
treating asthmatic attacks where the airways suddenly become so
constricted that the patient has difficulty in breathing) are best
delivered by inhalation directly to the lungs where they can rapidly
dilate the airways, rather than being swallowed in the form of tablet
with the consequent delay in action while the drug is absorbed and
delivered to the lungs
D R S P N A Y A K - P A R U L U N I V E R S I T Y 64
Examples for dosage forms cont.
65. BIOPHARMACEUTICS
The study of pharmaceutical factors which affect the fate of the drug after
administration is called biopharmaceutics and these factors will need to
be evaluated in the development of the new drug
To be effective, a drug must reach in desired concentration to the part of
the body where it is required to act and, ideally, must be maintained at
concentration for the appropriate period of time
D R S P N A Y A K - P A R U L U N I V E R S I T Y 65
66. BIOPHARMACEUTICS CONT.
This goal is influenced by the key interactions which take place between the drug
and the body after the drug has been administered
These are :
Absorption
Distribution
Metabolism
Elimination
D R S P N A Y A K - P A R U L U N I V E R S I T Y 66
67. PRODUCT STABILITY
After the dosage forms of the medicine have been chooses, stability
studies must be undertaken because manufacturers needs to know how
long their product remains therapeutically active in the packaging
material they intend to use
Any pharmaceutical product can be subject to chemical or
microbiological deterioration and the regulatory authorities will need to
be shown the manufacturer’s experimental evidence for their claimed
shelf-life of the product
If, for example, the medicine is principally going to be used in the tropics,
it should be able to withstand climatic conditions there for the duration
D R S P N A Y A K - P A R U L U N I V E R S I T Y 67
68. THANK YOU
ALL THE BEST..!
D R S P N A Y A K - P A R U L U N I V E R S I T Y 68