Surrogate endpoints are biomarkers intended to substitute for clinical endpoints and predict clinical benefit from a treatment. Regulatory agencies provide guidance on using surrogate endpoints for drug approval. The EMA and FDA may approve drugs based on surrogate endpoints that are reasonably likely to predict clinical benefit, but require post-marketing studies to verify the clinical benefit. The EMA guidance documents discuss considerations for various disease areas, noting surrogate endpoints must be validated and their relationship to clinical outcomes understood to support drug approval.
A surrogate endpoint is a physical measurement of a specific outcome which is considered to be a valid predictor (or representative) of the real outcome or final result.
Siro Clinical Research Institute
Overcoming the Challenges of Benefit Risk Assessment for Established ProductsSGS
Conducting/Implementing a benefit/ risk assessment can be very challenging for “old” established products. Scientific assessment on benefit/ risk is conducted based on the best evidence available. The main objective of this presentation is to discuss how this approach can be applied for different type of regulatory documents that are to be prepared for established products.
Describes in detail definition, purpose, participants and goal of good clinical practices (GCP). Gives history of GCP staring form Nuremberg code in 1948 to implementation of GCP guidance via WHO handbook in 2005. Also describes Nuremberg's code, declaration of Helsinki and Thirteen principles of GCP.
Lets, just get to know more about safety reporting in clinical trails with some terminologies, reporting requirements of ADR, compensations involved and finally the role of ethics committee in it,
A surrogate endpoint is a physical measurement of a specific outcome which is considered to be a valid predictor (or representative) of the real outcome or final result.
Siro Clinical Research Institute
Overcoming the Challenges of Benefit Risk Assessment for Established ProductsSGS
Conducting/Implementing a benefit/ risk assessment can be very challenging for “old” established products. Scientific assessment on benefit/ risk is conducted based on the best evidence available. The main objective of this presentation is to discuss how this approach can be applied for different type of regulatory documents that are to be prepared for established products.
Describes in detail definition, purpose, participants and goal of good clinical practices (GCP). Gives history of GCP staring form Nuremberg code in 1948 to implementation of GCP guidance via WHO handbook in 2005. Also describes Nuremberg's code, declaration of Helsinki and Thirteen principles of GCP.
Lets, just get to know more about safety reporting in clinical trails with some terminologies, reporting requirements of ADR, compensations involved and finally the role of ethics committee in it,
“CSR is a detailed regulatory document which gives the information about the methods and results (related to efficacy and safety) of a clinical trial. CSRs are created as a part of the process of submitting applications to the Regulatory Authorities for new medical treatments and for its approval. CSRs can be full, abbreviated, synopsis, supplementary, observational etc as per the results and requirements”.
Presented at PhUSE 2013
The evaluation of efficacy in oncology studies, in particular for solid tumors, is pretty standard and well defined by several regulatory guidance (e.g. EMA and FDA), including some specific cancer type guidance (e.g. NSCLC from FDA).
Although some references will be also given for non-solid tumors, the paper will mainly focus on solid tumors efficacy
endpoints.
Overall Survival, Best Overall Response as per RECIST criteria, Progression Free Survival (PFS), Time to Progression (TTP), Best Overall Response Rate are some of the key efficacy indicators that will be discussed.
General principles of Periodic Safety Update Reports(PSUR)Psur by Julia Appel...László Árvai
The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to Bluefish Pharmaceuticals.
The safety monitoring in a clinical trail accompanies by common practices in safety monitoring, communicating safety information among stakeholders in a clinical trail.
Table of contents
-Definition of CRF
-What is CRF
-Types & Methods of filling of CRF
-CRF Input team
-CRF Approval team
-Review team
-Facts about CRF
-Purpose of CRF
-CRF Development process & Guidelines
-Elements of CRF
-CRF Design
-CRF completion checklist
-CRF Design tools
-CRF use
-GCP connection
INSTITUTIONAL REVIEW BOARD (IRB/IEC).pptxRAHUL PAL
The International Council on Harmonisation (ICH) defines an institutional review board (IRB) as a group formally designated to protect the rights, safety and well-being of humans involved in a clinical trial by reviewing all aspects of the trial and approving its startup. IRBs can also be called independent ethics committees (IECs).
An IRB/IEC reviews the appropriateness of the clinical trial protocol as well as the risks and benefits to study participants. It ensures that clinical trial participants are exposed to minimal risk in relation to any benefits that might result from the research.
IRB/IEC members should be collectively qualified to review the scientific, medical and ethical aspects of the trial.
Per the FDA, an IRB/IEC should have:
At least five members.
Members with varying backgrounds.
At least one member who represents a non-scientific area (a lay member).
At least one member who is not affiliated with the institution or the trial site (an independent member).
Competent members who are able to review and evaluate the science, medical aspects and ethics of the proposed trial.
Causality Assessment in PharmacovigilanceClinosolIndia
Causality assessment is the process of determining whether a particular drug or medical intervention is the cause of an adverse event or reaction that has occurred in a patient. The following are some key principles and factors that are considered in causality assessment:
Temporal relationship: The timing of the adverse event in relation to the drug or intervention is a key factor in causality assessment. If the adverse event occurs shortly after the drug is administered or the intervention is performed, this may suggest a causal relationship.
Biological plausibility: The biological mechanisms by which the drug or intervention could cause the adverse event should be considered. If there is a plausible biological mechanism for the adverse event, this may support a causal relationship.
Alternative explanations: Other factors that could have caused the adverse event, such as pre-existing medical conditions, should be considered and ruled out before attributing the event to the drug or intervention.
Dose-response relationship: If there is a clear dose-response relationship between the drug or intervention and the adverse event, this may suggest a causal relationship.
Rechallenge: If the adverse event reoccurs when the drug or intervention is readministered, this may provide further evidence for a causal relationship.
There are several methods for conducting causality assessment, including the Naranjo algorithm, the World Health Organization-Uppsala Monitoring Centre (WHO-UMC) system, and the Liverpool Causality Assessment Tool (LCAT). These methods use different criteria and scoring systems to evaluate the likelihood of a causal relationship between the drug or intervention and the adverse event.
The aim of Safety reports is describe the safety during the lifecycle of the medicinal product. These reports are necessary during development as well as during the authorization process or renewal. In addition, several of these reports may be required by Health Authorities in case of safety concerns.
This presentation contains a full overview about periodic safety update reports and all the information related with it.
“CSR is a detailed regulatory document which gives the information about the methods and results (related to efficacy and safety) of a clinical trial. CSRs are created as a part of the process of submitting applications to the Regulatory Authorities for new medical treatments and for its approval. CSRs can be full, abbreviated, synopsis, supplementary, observational etc as per the results and requirements”.
Presented at PhUSE 2013
The evaluation of efficacy in oncology studies, in particular for solid tumors, is pretty standard and well defined by several regulatory guidance (e.g. EMA and FDA), including some specific cancer type guidance (e.g. NSCLC from FDA).
Although some references will be also given for non-solid tumors, the paper will mainly focus on solid tumors efficacy
endpoints.
Overall Survival, Best Overall Response as per RECIST criteria, Progression Free Survival (PFS), Time to Progression (TTP), Best Overall Response Rate are some of the key efficacy indicators that will be discussed.
General principles of Periodic Safety Update Reports(PSUR)Psur by Julia Appel...László Árvai
The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to Bluefish Pharmaceuticals.
The safety monitoring in a clinical trail accompanies by common practices in safety monitoring, communicating safety information among stakeholders in a clinical trail.
Table of contents
-Definition of CRF
-What is CRF
-Types & Methods of filling of CRF
-CRF Input team
-CRF Approval team
-Review team
-Facts about CRF
-Purpose of CRF
-CRF Development process & Guidelines
-Elements of CRF
-CRF Design
-CRF completion checklist
-CRF Design tools
-CRF use
-GCP connection
INSTITUTIONAL REVIEW BOARD (IRB/IEC).pptxRAHUL PAL
The International Council on Harmonisation (ICH) defines an institutional review board (IRB) as a group formally designated to protect the rights, safety and well-being of humans involved in a clinical trial by reviewing all aspects of the trial and approving its startup. IRBs can also be called independent ethics committees (IECs).
An IRB/IEC reviews the appropriateness of the clinical trial protocol as well as the risks and benefits to study participants. It ensures that clinical trial participants are exposed to minimal risk in relation to any benefits that might result from the research.
IRB/IEC members should be collectively qualified to review the scientific, medical and ethical aspects of the trial.
Per the FDA, an IRB/IEC should have:
At least five members.
Members with varying backgrounds.
At least one member who represents a non-scientific area (a lay member).
At least one member who is not affiliated with the institution or the trial site (an independent member).
Competent members who are able to review and evaluate the science, medical aspects and ethics of the proposed trial.
Causality Assessment in PharmacovigilanceClinosolIndia
Causality assessment is the process of determining whether a particular drug or medical intervention is the cause of an adverse event or reaction that has occurred in a patient. The following are some key principles and factors that are considered in causality assessment:
Temporal relationship: The timing of the adverse event in relation to the drug or intervention is a key factor in causality assessment. If the adverse event occurs shortly after the drug is administered or the intervention is performed, this may suggest a causal relationship.
Biological plausibility: The biological mechanisms by which the drug or intervention could cause the adverse event should be considered. If there is a plausible biological mechanism for the adverse event, this may support a causal relationship.
Alternative explanations: Other factors that could have caused the adverse event, such as pre-existing medical conditions, should be considered and ruled out before attributing the event to the drug or intervention.
Dose-response relationship: If there is a clear dose-response relationship between the drug or intervention and the adverse event, this may suggest a causal relationship.
Rechallenge: If the adverse event reoccurs when the drug or intervention is readministered, this may provide further evidence for a causal relationship.
There are several methods for conducting causality assessment, including the Naranjo algorithm, the World Health Organization-Uppsala Monitoring Centre (WHO-UMC) system, and the Liverpool Causality Assessment Tool (LCAT). These methods use different criteria and scoring systems to evaluate the likelihood of a causal relationship between the drug or intervention and the adverse event.
The aim of Safety reports is describe the safety during the lifecycle of the medicinal product. These reports are necessary during development as well as during the authorization process or renewal. In addition, several of these reports may be required by Health Authorities in case of safety concerns.
This presentation contains a full overview about periodic safety update reports and all the information related with it.
This ppt will provide you a brief yet effective information about major types of biomarkers, their definitions, their significance in disease dignosis & treatment, how they are being & are developed to be used as an effective dignostic tool for Cancer & their other future implications in other fields of medicine.
An overview of the ICH E9 guidance. Easy to follow, and I can provide a live presentation of this to your team! Great for those who are not familiar with statistics.
The Journal of Biomarkers in Drug Development (JBDD) promotes rigorous research that makes a significant contribution in advancing knowledge for Biomarkers in Drug Development. JBDD includes all major themes pertaining to Biomarkers used in Drug Development.
Regulatory guidelines for conducting toxicity studies by ichAnimatedWorld
ICH is the “International Conference on Harmonization of
Technical Requirements for Registration of Pharmaceuticals for
Human Use”
ICH is a joint initiative involving both regulators and research based industry representatives of the EU, Japan and the US in
scientific and technical discussions of the testing procedures required
to assess and ensure the safety, quality and efficacy of medicines
Biosimilaridad e intercambiabilidad: principios y evidencia: una revisión sis...Rosmirella Cano Rojas
Existen importantes lagunas en la evidencia sobre la seguridad de cambiar entre productos biológicos y sus biosimilares. Se necesitan ensayos clínicos y de farmacovigilancia suficientemente potenciados y adecuadamente analizados estadísticamente , con seguimientos a largo plazo y múltiples cambios, para respaldar la toma de decisiones sobre el cambio biosimilar.
Epidemiology is the study of occurrence, distribution and determinants of health and
diseases or disorders in man and its application in controlling health problems.
Epidemiology has by tradition two major areas.
First is the study of infectious diseases that spread to large populations, i.e., epidemics.
The second is the study of chronic diseases.
Epidemiological studies help to solve such health problems and provide a basis for
improving living conditions of the people.
During its progress and development, epidemiology has made available precise and
strict methodologies for the study of diseases.
Pharmacology is the study of the effects of drugs.
Clinical Pharmacology is the study of the effects of drugs in humans, It is traditionally
divided into two basic areas namely:
1. Pharmacokinetics
2. Pharmacodynamics.
Pharmacokinetics is the study of the relationship between dose administered of a drug
and the serum or blood level achieved, it deals with absorption, distribution, metabolism
and excretion.
Epidemiology is the study of the distribution and determinants of diseases in
populations.
Epidemics is the study of chronic/ infectious diseases in large populations.
Pharmacoepidemiology is the study of the use of and the effects of drugs in large
number of people.
It involves the examination of a single individual or large groups of people followed for
many years.
It involves gathering & analysis of information in order to identify possible causation &
related factors, that can be applied in clinical practice to group of people & also to
individuals undergoing treatment.
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
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
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.
MANAGEMENT OF ATRIOVENTRICULAR CONDUCTION BLOCK.pdfJim Jacob Roy
Cardiac conduction defects can occur due to various causes.
Atrioventricular conduction blocks ( AV blocks ) are classified into 3 types.
This document describes the acute management of AV block.
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.
3. regulatory drivers requirements guidelines… assessments… expectations practices interpretation precedents information (available to anyone) experience & analysis
4. Definitions Biomarker: objectively measured and evaluated indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. Pharmacodynamic marker reflects a pharmacologic response Clinical endpoint: a characteristic or variable that reflects how a patient feels, functions, or survives. Surrogate endpoint: a biomarker that is intended to substitute for a clinical endpoint; it is expected to predict clinical benefit (or harm or lack of benefit or harm). Source: Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin. Pharmacol. Ther. 2001 Mar;69(3):89-95.
5. How they relate Source: EMEA/CHMP Workshop on Biomarkers, 16 December 2005; Daniel Brasseur, CHMP atEMEA http://www.ema.europa.eu/pdfs/human/biomarkers/01BRASSEUR.pdf
7. EMA on biomarkers December 2005: EMEA biomarkers workshops with academia and healthcare professionals December 2006: EMEA biomarkers workshops with the EFPIA and with all stakeholders July 2008: First EMEA-FDA joint biomarkers qualification process Source: Human Medicines - Medicines and Emerging Science - Biomarkers [Internet]. [cited 2010 Jun 3]; Available from: http://www.ema.europa.eu/htms/human/mes/biomarkers.htm
8. Some relevant EMA guideances Guideline on clinical trials in small populations (CHMP/EWP/83561/2005) Note for guidance on clinical investigation of medicinal products in the treatment of lipid disorders (CPMP/EWP/3020/03) Concept paper on the need for an addendum on the clinical investigation of medicinal products intended for treatment of glucocorticoid-induced osteoporosis (EMA/CHMP/EWP/15912/2010) Guideline on medicinal products for the treatment of alzheimer’s disease and other dementias (CPMP/EWP/553/95) Note for guidance on clinical investigation of medicinal products in the treatment of hypertension (CPMP/EWP/238/95) Note for guidance on clinical evaluation of new vaccines (CPMP/EWP/463/97) Guideline on clinical investigation of medicinal products used in the treatment of osteoarthritis (CPMP/EWP/784/97) Guideline on the evaluation of medicinal products in the treatmentof primary osteoporosis (CPMP/EWP/552/95)
9. Guideline on clinical trials in small populations (CHMP/EWP/83561/2005) “surrogate markers as substitutes for a clinical endpoint may be considered” “The term ‘surrogate endpoint’ should only be used for biomarkers, which have been validated.” “selection of a surrogate marker as study endpoint requires it to be reasonably likely – based on epidemiologic, pathophysiologic, or other evidence – to predict benefit” “Considerations should include: How closely changes in the surrogate endpoint are causallylinked to changes in a clinical endpoint or symptom. How much risk is associated with the therapy What other therapies (if any) are available for the same condition.” “surrogate markers cannot serve as final proof of clinical efficacy or long-term benefit” “Surrogate endpoints may be acceptable but need to be fully justified. Their relation to clinical efficacy must be clear so that the balance of risks and benefits can be evaluated.”
10. Note for guidance on clinical investigation of medicinal products in the treatment of lipid disorders (CPMP/EWP/3020/03) Although ideally a new lipid-modifying agent is expected to demonstrate an effect on the prevention of cardiovascular morbidity and mortality, a relative reduction in LDL cholesterol is acceptable in patients with primary hypercholesterolemia as a valid surrogate endpoint, provided that no claims are made regarding morbidity and mortality. However, an isolated effect on these parameters is in principle not expected to be the sole basis for the demonstration of the efficacy of a new lipid-modifying agent, but should be seen in conjunction with the effect on non-HDL cholesterol and the underlying mechanism as well. A new lipid modifying agent is only acceptable for registration when there is no suggestion of a detrimental effect on both cardiovascular and non-cardiovascular mortality and morbidity.
11. Concept paper on the need for an addendum on the clinical investigation of medicinal products intended for treatment of glucocorticoid-induced osteoporosis (EMA/CHMP/EWP/15912/2010) Points to be addressed in the addendum include: the need to use placebo-controlled studies with fracture as a primary endpoint or to use bone mineral density, or even other biochemical endpoints, as an acceptable surrogate endpoint;
12. Note for guidance on clinical investigation of medicinal products in the treatment of hypertension (CPMP/EWP/238/95) The goal of treating hypertension is to prevent morbidity and mortality associated with high blood pressure. Reduction in blood pressure has usually been accepted as a valid surrogate endpoint in order to assess whether this goal can be achieved by an antihypertensive agent. Notwithstanding, even if an antihypertensive effect has been proven, a new antihypertensive agent is only acceptable for registration when there is no suspicion of a detrimental effect on mortality and cardiovascular morbidity.
13. Guideline on medicinal products for the treatment of alzheimer’s disease and other dementias (CPMP/EWP/553/95) To be accepted as a surrogate endpoint such a biomarker ideally should respond to treatment, predict clinical response and be compellingly related to the pathophysiological process of the dementing condition. However, careful and sufficient validation of the proposed biomarkers as a potential surrogate endpoint is a prerequisite for acceptanceby regulatory bodies.
14. Note for guidance on clinical evaluation of new vaccines (CPMP/EWP/463/97) Vaccine efficacy may be evaluated and assessed either on the basis of clinical (protection) endpoints and/or validated serological surrogate endpoints whenever appropriate. When efficacy assessment in equivalence trials is based upon immunological surrogate parameters the relationship between the surrogate endpoint and the clinical endpoint must be taken into consideration, since this does not necessarily have to be a linear relationship.
15. Guideline on clinical investigation of medicinal products used in the treatment of osteoarthritis (CPMP/EWP/784/97) MRI measures may be an acceptable surrogate endpoint when their clinical relevance has been shown.
16. Guideline on the evaluation of medicinal products in the treatmentof primary osteoporosis (CPMP/EWP/552/95) Alternative surrogate endpoints like biochemical markers of bone turnover should also be used in bridging studies after a thorough analysis of historical studies showing a good correlation between pharmacokinetic exposures, the pharmacodynamic response and the reduction in fracture risk. To avoid having to conduct separate fracture studies, the time-course of changes in surrogate markers should recapitulate the time-course observed for the original dosing regimen. This should apply to any surrogate endpoint that is known to be associated with fracture risk, such as BMD and/or a biochemical marker.
17. The ENHANCE trial:MHRA statement (2008) The results showed that patients assigned simvastatin plus ezetimibehad significantly lower mean LDL cholesterol than did those assigned simvastatinplus placebo at the end of the study (3·65 mmol/L [SD 1·36] vs 4·98 mmol/L [SD 1·56]; difference between groups 16·5%, p<0·01). However, mean change in intima–media thickness of the carotid artery did not differ significantly between groups (0·0111 mm [SE 0·0038] vs 0·0058 mm [SE 0.0037], respectively, p=0·29). To date, no data from large clinical outcomes trials are available for ezetimibe. The ongoing IMPROVE-IT trial (IMProved Reduction of Outcomes: VytorinEfficacy International Trial) is evaluating the clinical benefit—in terms of cardiovascular morbidity and mortality—of ezetimibe combined with simvastatin compared with simvastatinalone in about 10 000 patients with acute coronary syndromes. However, the results are not expected to be available in the next 4 years. The MHRA, together with other regulatory agencies in the European Union, is currently reviewing the results of the ENHANCE trial to establish their clinical significance and potential effect on the balance of benefits and risks for ezetimibe. We will inform healthcare professionals of any changes to prescribing advice as soon as these reviews have been completed. A couple of useful links: http://j.mp/cjyk5p; http://j.mp/aeOS47
18. FDA on surrogate endpoints 21CFR314.510 (April 2009) Subpart H: Accelerated Approval of New Drugs for Serious or Life-Threatening Illnesses Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or irreversible morbidity. FDA may grant marketing approval for a new drug product on the basis of adequate and well-controlled clinical trials establishing that the drug product has an effect on a surrogate endpoint that is reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict clinical benefit or on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity. Approval under this section will be subject to the requirement that the applicant study the drug further, to verify and describe its clinical benefit, where there is uncertainty as to the relation of the surrogate endpoint to clinical benefit, or of the observed clinical benefit to ultimate outcome. Postmarketing studies would usually be studies already underway. When required to be conducted, such studies must also be adequate and well-controlled. The applicant shall carry out any such studies with due diligence.
19. So what does all this mean? There is much uncertainty – lots of maybes Surrogate endpoints must be predictive of intended clinical benefit Surrogate endpoints must be fully justified Surrogate endpoints must be adequately validated Further evidence is often required (e.g. post-marketing studies) Because of uncertainties Scientific Advice or Protocol Assistance are essential hint: “For more information on biomarkers, see: Scientific Advice and Protocol Assistance”
20. A view from the EMA Decisions taken during the process of marketing authorisation of medicinal products are always uncertain. Evidence that is “beyond doubt” never exists. Long life to the biomarkers.Bruno Flamion, Chair, Scientific Advice Working Party (SAWP) at the 2005 workshop