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.
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.
The safety monitoring in a clinical trail accompanies by common practices in safety monitoring, communicating safety information among stakeholders in a clinical trail.
Clinical study on human subjects according to all guidelines to form a ideal protocol and requirement to conduct clinical trial with very efficient way mainly considering to India and ICH associated countries
When a new drug/device/surgical procedure/treatment or other potential medical innovation is developed it must be thoroughly tested to ensure that it is safe and does what it is supposed to be.
This presentation will provide a basic overview of clinical research process.
The Investigator's Brochure (IB) is a comprehensive document summarizing the body of information about an investigational product (IB) obtained during a drug trial.
Regulations for drug approval in USA, E.U & India
Pharmaceutical industry is the most regulated of all the industries. Regulations are put in order to develop the most efficient and safe pharmaceutical products. It takes more than 8 to 15 years to develop a new drug product & costs more than $ 800 million.
Abbreviated New Drug Application [ANDA]Sagar Savale
An Abbreviated New Drug Application (ANDA) contains data which when submitted to FDA's CDER, Office of Generic Drugs, provides for the review and ultimate approval of a generic drug product.
Regulation in clinical trial, Schedule Y and recent amendmentsDr. Siddhartha Dutta
Regulatory framework of India, Acts and Regulations for conduct of clinical trial in India, Schedule Y, approval of new chemical entity and recent amendments
Bioavailability and Bioequivalence StudiesPranav Sopory
BA and BE studies.
Seminar presented in All India Institute of Medical Sciences (AIIMS - New Delhi).
Focus in Pharmacokinetic parameters (Cmax, AUC)
Single dose PK study, Steady state PK study, Modified drug release PK study, In vivo mechanisms, invitro mechanisms, Pharmacodynamic Study, Comparatice Clinical Trials. Biowavers and Biosimilimars.
Reference: CDSCO guideline, USFDA guideline, ICH guidelines
The NDA application is the vehicle through which drug sponsors, such as biotech and pharmaceutical companies, formally propose that the FDA approve a new pharmaceutical for sale and marketing
The safety monitoring in a clinical trail accompanies by common practices in safety monitoring, communicating safety information among stakeholders in a clinical trail.
Clinical study on human subjects according to all guidelines to form a ideal protocol and requirement to conduct clinical trial with very efficient way mainly considering to India and ICH associated countries
When a new drug/device/surgical procedure/treatment or other potential medical innovation is developed it must be thoroughly tested to ensure that it is safe and does what it is supposed to be.
This presentation will provide a basic overview of clinical research process.
The Investigator's Brochure (IB) is a comprehensive document summarizing the body of information about an investigational product (IB) obtained during a drug trial.
Regulations for drug approval in USA, E.U & India
Pharmaceutical industry is the most regulated of all the industries. Regulations are put in order to develop the most efficient and safe pharmaceutical products. It takes more than 8 to 15 years to develop a new drug product & costs more than $ 800 million.
Abbreviated New Drug Application [ANDA]Sagar Savale
An Abbreviated New Drug Application (ANDA) contains data which when submitted to FDA's CDER, Office of Generic Drugs, provides for the review and ultimate approval of a generic drug product.
Regulation in clinical trial, Schedule Y and recent amendmentsDr. Siddhartha Dutta
Regulatory framework of India, Acts and Regulations for conduct of clinical trial in India, Schedule Y, approval of new chemical entity and recent amendments
Bioavailability and Bioequivalence StudiesPranav Sopory
BA and BE studies.
Seminar presented in All India Institute of Medical Sciences (AIIMS - New Delhi).
Focus in Pharmacokinetic parameters (Cmax, AUC)
Single dose PK study, Steady state PK study, Modified drug release PK study, In vivo mechanisms, invitro mechanisms, Pharmacodynamic Study, Comparatice Clinical Trials. Biowavers and Biosimilimars.
Reference: CDSCO guideline, USFDA guideline, ICH guidelines
The NDA application is the vehicle through which drug sponsors, such as biotech and pharmaceutical companies, formally propose that the FDA approve a new pharmaceutical for sale and marketing
Assignment on Experimental Study- RCT and Non RCT, Observation Study: Cohort, Case Control, Cross sectional, Roles and responsibilities of Clinical Trial Personnel: Investigator, Study Coordinator, Sponsor, Contract Research Organization and its management Guidelines to the preparation of documents, Preparation of protocol, Investigator Brochure, Case Report Forms, Clinical Study Report Clinical Trial Monitoring-Safety Monitoring in CT
Detailed idea on nanotechnology, nanomedicine, types, uses, pharmacotherapy, and future prospects of the nanotechnology. Drug delivery systems, Pharmacokinetics and pharmacodynamics of the nanoparticles are dealt in detail
An intensive material on the anticancer agents. Detailed idea of the various classes of anticancer and recent advances in each class. Newer anticancer drug delivery systems and the anticancer vaccines are also dealt in detail.
An intensive material on recent advances on contraception including the current contraceptive methods and a brief overview on immunocontraception and contraceptive vaccines
A concise overview of pharmacoeconomics, health economics, various costs, various pharmacoeconomic study designs and its application in the field of medicine and drug development
A concise overview of biased agonism, mechanism, beta arrestin pathway, types, examples, GPCR, pros and cons of biased agonism, beta blockers and angiostensin receptor in biased agonism.
Receptor types, mechanism, receptor pharmacology, drug receptor interactions, theories of receptor pharmacology, spare receptors and new concepts like biased agonism
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.
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Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
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Pulmonary Thromboembolism - etilogy, types, medical- Surgical and nursing man...VarunMahajani
Disruption of blood supply to lung alveoli due to blockage of one or more pulmonary blood vessels is called as Pulmonary thromboembolism. In this presentation we will discuss its causes, types and its management in depth.
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
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.
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
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New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
Prix Galien International 2024 Forum ProgramLevi Shapiro
June 20, 2024, Prix Galien International and Jerusalem Ethics Forum in ROME. Detailed agenda including panels:
- ADVANCES IN CARDIOLOGY: A NEW PARADIGM IS COMING
- WOMEN’S HEALTH: FERTILITY PRESERVATION
- WHAT’S NEW IN THE TREATMENT OF INFECTIOUS,
ONCOLOGICAL AND INFLAMMATORY SKIN DISEASES?
- ARTIFICIAL INTELLIGENCE AND ETHICS
- GENE THERAPY
- BEYOND BORDERS: GLOBAL INITIATIVES FOR DEMOCRATIZING LIFE SCIENCE TECHNOLOGIES AND PROMOTING ACCESS TO HEALTHCARE
- ETHICAL CHALLENGES IN LIFE SCIENCES
- Prix Galien International Awards Ceremony
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
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.
2. Introduction
Drug Discovery & Development
Phases of clinical trial-O, I, II, III, IV
Pre-requisites & Objectives
Phase 5
Conclusion
3. First controlled clinical trial
on 12 Sailors -Scurvy
Clinical Trial by James
Lind
1747 – Lind’s study
comparing the use of limes
and oranges in the
treatment of scurvy
1948-First randomized
controlled clinical trial in
Medical Research Council
TB Unit, Brompton
Hospital, UK
First use of a randomized
control group: streptomycin
James Lind
4. CLINICAL TRIAL
“CLINICAL TRIAL” is a systematic study of new
drug in human subjects to generate data for
discovering and/or verifying the clinical,
pharmacological and adverse effects with the
objective of determining safety and efficacy of the
new drug.
5. Criteria Last century Present era
Animal use Frequent Relatively less
Ethical
Considerations
Less stringent More Stringent
No. of
Compounds
explored
Less More
No. of Targets
explored
Less More
Terminology Drug discovery Drug development5
6.
7. DRUG/DEVICE TRIALS- A
CUMBERSOME PROCESS
Target a subset of the population, means not everyone can
participate
Appropriate patients and obtain their consent, especially
when they may receive no direct benefit
Requires patients to have unusual combinations of disease
characteristics
For chronic conditions like cancer, it takes months, if not
years, to monitor efficacy
For drugs that are not expected to have a strong effect
recruiting enough patients to test the drug's effectiveness can
take several years
8. New drug ready to be studied in humans a Notice of
Claimed Investigational Exemption for a New Drug (IND)
must be filed with the FDA
It includes :-
1. Info. on the composition and source of the drug
2. Chemical and manufacturing information
3. Animal studies data
4. Proposed plans for clinical trials
5. Names and credentials of physicians who will conduct the
clinical trials
6. A compilation of the key data relevant to study of the drug
in humans that has been made available to investigators
and their institutional review boards
11. Exploratory, first-in-human trials conducted in accordance
with the USFDA 2006 Guidance on Exploratory IND Studies
Limited human exposure
No therapeutic or diagnostic intent
Assists in GO vs. NO GO decision early in development
process
Single sub-therapeutic dose of the NCE to gather preliminary
data on the agent's PK/PD before initiating phase 1 testing
13. 10 to 15 healthy volunteers
Limited dosing duration ≤ 7 days
Very low doses (1/100th of estimated
human dose or max. of 100 µg total
dose of candidate drug)
No data on safety or efficacy, being
by definition a dose too low to cause
any therapeutic effect
Phase 0 clinical trial are not
mandatory
14. ADVANTAGES
DISADVANTAGE
S
• No data on
safety or
efficacy
• Ethical concerns
PK & PD on human
subjects
Elaborate animal
studies & costly
phase I human trials
could be avoided for
candidate drugs
Regulatory
flexibility
Data helps to
prioritize promising
compounds
Useful in more
precise selection of
doses for & modify
phase 1 design
20. Single ascending dose
Phase 1a
• Small group of subjects given
single dose of drug and
observed for a period of time
• If PK data is in line with
predicted safe values, the dose
is increased in a new group of
subjects
• Continued till maximum
tolerated dose (MTD) is
defined
Multiple Ascending dose
Phase 1b
A group of subjects receives
multiple low doses of the drug
Samples (of blood and other body
fluids) collected at various time
points and analyzed
Gives better understanding of
PK/PD & safety of the drug
21.
22. REGULATIONS WITH PHASE 1
Schedule-Y (2005 amendment) of the Drugs and Cosmetics
Rules made parallel trials possible in India
Documents to be submitted before commencing phase I trials
1) All documents of pre-clinical data.
2) Plans, protocols and CRF ’s for phase I studies.
3) Name, address and bio-data of investigator.
4) Agreement from the sponsors to inform the drug controller
of any adverse reaction’s occurring during ongoing
animal/human studies.
5) Nature of ‘informed consent’
6) Agreement to submit annual progress report.
23. Assessment of data and expert consultation are done to decide
the role of drug in adverse event and study continuation
Serious toxicity is rare and needs judgment for proceeding
Interpretation, of clinical and lab deviations, from normal
range needs to be done, and within subject comparison, of
data is mandatory
24.
25. Therapeutic
exploratory trial
100-300 Patients
Confirm the
hypothesis
conceptualised
Dose response
determination
Determine potential
end points
Types of patients and
specific indications
Determine of target
population
Determine dose
regimen
Safety
Drug
Interaction
s
Efficacy
26. Series of doses of varying strengths may be used in phase II
trials to determine the effective dose, dosing regimen
frequency and duration
Comparator –standard treatment or placebo
Controlled Single Blind RCT
End points :-
1. Definitive end point
Measures drug effect directly—cancer(mortality), Pain
relief (analgesic), HTN(stroke)
2. Surrogate end point
Predictive of the definitive end point --Reduction in tumor
size (anticancer) or cancer-associated proteins p53, TGF-α
and BP or cholesterol level in HTN
28. Phase 2 A
Proof of
concept
Pilot
trials
Up to 200
patients
Therapeutic
efficacy
Single
blind,
parallel
group
Dose
response &
dose range
for phase 2b
32. Pt. grp.
(randomi
zed)
Week 1 Week 2 Week 3
I Standard
drug
Placebo New drug
II Placebo New
drug
Standard
drug
III New drug Standar
d drug
Placebo
33. Determine dosage schedule, that demonstrates
adequate efficacy and safety
Identify disease subtype, where drug is
effective (or ineffective)
Comparison PK/PD with other standards
Evaluation of special population (e.g. elderly,
renally impaired, etc)
34. Peri-approval studies
Not a part of regulatory dossier
Study drug vs. market leader
Cost value arguments
Assess QOL & Pharmacoeconomics studies
38. Non-interventional study mandated by regulatory authorities
to verify the safety, tolerability and effectiveness of a
marketed drug in a particular population
Open studies where unlike pre-marketing studies, no strict
inclusion & exclusion criteria, but governed by the
permissible indications and contra-indications of the drug as
stated in prescribing information
PMS studies exemplify the difference b/w EFFICACY and
EFFECTIVENESS
PSURs
SUSAR(Serious and unexpected suspected adverse reactions)
39. Describe how a drug is marketed, prescribed, and used in a population,
and how these factors influence outcomes, including clinical, social, and
economic outcomes
These studies provide data on specific populations, such as the elderly,
children, or patients with hepatic or renal dysfunction, often stratified by
age, gender, concomitant medication, and other characteristics.
DUS have been used to describe the effect of regulatory actions and media
attention on the use of drugs, as well as to develop estimates of the
economic burden of the cost of drugs.
DUS can be used to examine the relationship between recommended and
actual clinical practice
These studies can help to determine whether a drug has the potential for
drug abuse
limitations include a lack of clinical outcome data or information of the
indication for use of a product.
40. PHASE V
Pragmatic trial/ translational research
Designed to test interventions in the full spectrum of everyday clinical
settings in order to maximize applicability and generalizability.
Research question- whether an intervention actually works in real life??
Moves from the researcher’s bench to the patient’s bedside
Idea is to analyze the data of the drug which is in wide spread use to
maximize its benefits so that it can be used for the betterment of broader
sections of community
It is used to signify the integration of a new clinical treatment into
widespread public health practice
Editor's Notes
In the1700s, scurvy was a particularly vexing problem on the long voyages across the Atlantic Ocean.
reviewed the existent literature of the time. In so doing, he found a report from 1600 that stated ‘1 of 4 ships that sailed on February 13th, 1600, was supplied with lemon juice, and almost all of the sailors aboard the one ship were free of scurvy, while most of the sailors of the other ships developed the disease.
1747, while serving as surgeon on HMS Salisbury, he carried out experiments to discover the cause of scurvy, the symptoms of which included loose teeth, bleeding gums and hemorrhages.
6 pairs, each group different additions +basic diet.
Some were given cider, seawater, mixture of garlic, mustard & horseradish. spoonfuls of vinegar, and the last two oranges and lemons
One of the two recovered quickly and was fit for duty after 6 days, while the second was the best recovered and was assigned the role of nurse for the remaining patients
Bradford Hill-study of streptomycin in pulmonary tuberculosis
conducted to allow safety and efficacy data for new drugs or devices.
can only take place once satisfactory informn is gathered on quality of the product and its non-clinical safety, and Health Authority/Ethics Committee approval
can vary in size from a single center in one country to multicenter trials in multiple countries
CT- small part of the research that goes into developing a new treatment.
Potential drugs, first discovered, purified, characterized, and tested in labs, (in cell, and animal studies) before ever undergoing clinical trials.
about 1k potential drugs are tested before 1 reaches CT
(meaning a large number of patients must be recruited to observe any effect), (i.e., getting statistical power)
It is a challenge to find the appropriate patients and obtain their consent, especially when they may receive no direct benefit (because the study drug is not yet proven to work, or the patient may receive a placebo).
Clinical trials that do not involve a new drug usually have a much shorter duration
Almost 40% of Phase 1 failures are thought to be due to PK issues
Human Microdosing aims to reduce the resources spent on non-viable drugs
Using human models rather than relying on the animal data helps us to confirm end points
label a candidate drug-radioisotope carbon-14, and then administer the compound to human volunteers,
at levels typically about 100 times lower than the proposed therapeutic dosage. (f1, to 100 mcgrams).
As only microdose levels of the drug are used, analytical methods are limited.
Extreme sensitivity is needed. AMS, i.e. accelerator mass spectrometry is the m/c method for microdose analysis.
sensitivity of picogram to attogram range, and AMS still continues to be more sensitive than the most sensitive LC/MS/MS machines
Exploratory FIH studies at pharmacologic dose have particular utility where the PK/PD profile will facilitate informed decision
making and can offer either early program termination or rapid progress to phase II
Developed by FDA & EMA as “cost-cutting” tools They are case to case based.
no concept of Phase 0 or any other equivalent of an Exploratory IND in Indian regulation.
particularly oral bioavailability and half-life of the drug
Pharmacok worked out using AMS with radiolabelled drug/LC-MS to measure ultra low drug levels
Shorten drug development timeline by reducing chances of failure in subsequent phases
No benefit to participants-where as reqrd to give blood samples/ biopsy for PK/PD analysis
Human pharmacology studies
Test drug is too toxic to be tested in healthy volunteers
E.g anticancer drugs, HIVbiologics
Therapeutic range/ratio is too narrow to test
(e.g. Antiarrhythmic)
Dose in patient > Normal Volunteers can tolerate
(e.g. Neuroleptics)
PK issues are addressed metabolism of a newer anti epileptic whose microsomal enzymes are already induced by an anti epileptic drug.
dose escalation studies, so that the best and safest dose can be found and to discover the point at which a compound is too poisonous to administer
Single ascending dose & multiple ascending dose studies
Ex: 1) dose tolerance studies
2) SAD/MAD PK/PD studies
3) drug interactions
Safety (Drug affects CV, hepatic or renal functions adversely)
Tolerability (Drug produces unpleasant symptoms like headache, nausea & vomiting)
whether humans & animals show significant pharmacokinetic differences Whether deficiency in drug effect is due to lack of absorption / faster elimination)
Begin with 1/5th or 1/10th of MTD in animals & calc. it for 70 kg body wt.)
Detect any predictable toxicity
Volunteers are paid an inconvenience fee for their time spent
Maximum tolerated dose
Nature of adverse reactions that can be expected
Preliminary characterization of the drug
Accumulation of parent drug/ metabolites
Bioavailability in presence of food
Drug - drug interaction ( mostly parallel to phase II)
MAD- dose and dosing frequency r chosen in order to attain therapeutic drug levels of drug in the blood which is maintained in steady state level foe several days to assess the safety parameters
If accumulation on multiple administration
Single blinded placebo controlled to determine whether effects observed are due to the study drug or environmental conditions & to allow informed decision on dose escalation, with safety and PK data being available for investigator review.
Food effect –fast and fed state, standard diet given , act as their own control
“Schedule of drug administration in Phase I is determined from the preclinical testing”
“Investigator(s) report all sae to the Sponsor -24 hours and to the EC within 7 working days of their occurrence”.
Sponser- 14 calendar days would be communicated to the local regulatory authority & other PI
Cmax Peak drug &/or metabolite concentration
Tmax Time to peak drug &/or metabolite conc.
AUC0-∞ Area under conc.-time curve e.p. to inf.
AUC0-T AUC calc. to a specific time point T
T1/2 Time taken for level of drug to dec. by 1/2
VD Volume of distr.
CL Clearance
MRT Mean residence time (Avg. time a drug molecule rem. In body after rapid i.m. injection)
Drugs and Cosmetics Rules, phase I trials are not normally permitted for foreign companies and is usually reserved for the new drug substances discovered in India.
Regulatory fees payable to the DCGI’ s office for reviewing submitted documents is Rs. 50,000/- for phase I studies. Application is to be submitted to the Drugs Controller General (India)
If investigational drug is responsible for an adverse event, subsequent administration has to be prevented
major challenge in new drug testing
Main purpose Gather evidence that drug has effects suggested by preclinical trials
designed to assess how well the drug works, as well as to continue Phase I safety assessments.
Drug studied for 1st time in pts. with target disease
risk-benefit profile has to be assessed, as to whether the trial should use placebo or standard treatment, to ensure the subjects’ well being is not compromised during the tria
Specific clinical endpoints or markers are used to assess interaction of drug and disease
with IIb, being an extension to the safety and efficacy studies assessed in IIa.
Primary goal: To determine the evidence of therapeutic efficacy & safety.
Pilot trials: Dose response determination, determine dose regimen and determination of target population.
Establishment of dose range for more definitive therapeutic trials in phase Iib
Proves primary hypothesis
Efficacy
Effect Size
Adverse events (ADR of special interest)
Biomarker profiling
Pivotal- it can make or break the success of the drug
Test different doses and find optimal dose
Type of patients more responsive to treatment.
Placebo/Active controlled criteria
Tight inclusion and exclusion criteria
Multi-centre /Multinational trial
Dose-response
Frequency
Additional ADR
Identifying confounding factors
Out of all the drugs which enter phase 1only 1/3 of drugs ever make it to Phase III clinical trialsal most 80% of those that do enter Phase III trials move on to Phase IV trials.
Extended Clinical Trials- confirm efficacy in large pt grp
difficult trials to design and run, especially in therapies for chronic medical conditions.
Conducted in patients in whom the drug will be eventually intended. Eg. Mild Moderate severe
Inclusion and exclusion criteria relatively relaxed
Different dosages and combinations with other drugs
Subjects: large.
Trial design: open level or single or double blinded.
Multicenter.
Testing different stages of the disease indication.
Dosage forms , formulation
Different routes.
Conducted predominantly for marketing purposes
Comparator is market leader-in hope to achieve a benefit over & above the existing drug
This enables marketing & sales group to maximize the performance after launch
Phase 3b: Phase III trials will continue while the regulatory submission is pending at the appropriate regulatory agency. This allows patients to continue to receive possibly lifesaving drugs until the drug can be obtained by purchase. i.e. Antiretroviral, Anticancer etc.
.
Inclusion/exclusion criteria are not stringent, wider patient population.
Interaction with other drug if not tested earlier
Rare adverse effects Eg. Immunogenicity.
Long Term adverse effects on larger population for longer period. cerivastatin ,troglitazone rofecoxib
New use- detected by a chance discovery aspirin antiplat
Route- nimusulide rectal
Special population groups such as pregnant women
1 mandated by RA to be conducted as observational studies in a naturalistic setting - PMS
2 Phar epidemio- outcome research studies- morbidity/mortality studies
cost-minimization analysis, cost-benefit analysis, cost-effectiveness analysis or cost-utility analysis. Quality-adjusted life years
DUS- how a drug is marketed, prescribed, used in populn and how these factors influence clinical, social and economic outcomes
Case-con- retrospective evaluation- rare SE eg- thrmphlebits/TE by ocp
RA now insisting on sponsers to carry premarketing p 3 which mimics real world scenario- greater confidence before approval
adv- minimize drug withdrawl disadv- delay launch, costly drug
Efficacy is judged within the controlled environment of a clinical trial with strict inclusion and exclusion criteria and close monitoring and ensured compliance.
Effectiveness is the real test of a drug when it is used in a much larger population, with varied organ system function, concomitant drugs and where monitoring and compliance are not always ensured.
With these confounding factors when drug shows its effect its effectiveness
(SUSARs) are reported to RA on a continual basis and non-serious ones are compiled and reported periodically.
DUS can be used to determine if a product is being used in these populations. From these studies denominator data can be developed for use in determining rates of adverse drug reactions
drug abuse by examining whether patients are taking escalating dose regimens or whether there is evidence of inappropriate repeat prescribing
clinical trials typically exclude from study participation women who are pregnant or breastfeeding; therefore, PMS is the only means of obtaining information on mutagenic and teratogenic effects of drugs in humans.
Other special populations that benefit from PMS include the elderly and patients with multiple comorbidities. Like pregnant women, patients who are very old or very sick are excluded from premarketing trials.
Phase IV trials include additional drug-drug interaction(s), dose-response or safety studies and trials designed to support use under the approved indication(s), e.g. mortality/morbidity studies, epidemiological studies etc. all phase IV studies require permission from DCGI office. These trials go beyond the prior demonstration of the drug’s safety, efficacy and dose definition.
Not all Phase IV studies are post-marketing surveillance (PMS)
studies but every PMS study is a phase IV study. Phase IV is also an
important phase of drug development. In particular, the real world
effectiveness of a drug as evaluated in an observational, noninterventional
trial in a naturalistic setting which complements
the efficacy data that emanates from a pre-marketing randomized
controlled trial (RCT).True safety profile of a drug is characterized
only by continuing safety surveillance through a spontaneous
adverse event monitoring system and a post-marketing
surveillance/non-interventional study. Surveillance of
spontaneously reported adverse events continues as long as a
product is marketed. And so Phase IV in that sense never ends.
Not a legal/std terminology
None of the stand guidance documents mentions about this
Research aimed at enhancing the adoption of best practices in the community research findings like Community clinical epidemiology, health services (outcomes) research, Cost-effectiveness of prevention and treatment strategies
Basic results in gen knwledg and understanding of nature and its laws.
provides the means of answering a large number of important practical problems,
though it may not give a complete specific answer to any one of them
Clinical- Patient-oriented res. Epidemiologic and behavioral, Outcomes & health services res.