1. SCHEDULE Y
REGULATORY TOOL TO MANAGE RISK
11/12/2018

2. IEC BENEFITS RISKS SCENARIO FOR TODAY’S DISCUSSION: Schedule Y
SCOPE
UTILITY
NEW DRUG
DEVELOPMENT
PROCESS IN INDIA
RIGHTS SAFETY WELL BEING OF HUMAN SUBJECTS
Risk:To Human Subject:Harm to subject
To Research :Decline in clinical research because of regulatory burden
To Reputation of organisation:because of harm to subjects;incompetent
investigators,poor dissemination of data
Risk:Probability of Harm
Hazard:Occurrence of Harm
Risk Assessment=Impact of occurrence* Likelihood of occurrence
FUTURE DIRECTION
BENEFITS
RISKS
11/12/2018

3. SCHEDULE Y DEFINE NEW DRUG
SCOPE:REGULATE THEIR INTRODUCTION BASED ON SAFETY AND EFFICACY CONSIDERATIONS
ENSURE QUALITY
IMPLEMENTATION
11/12/2018

4. SCHEDULE Y NEW DRUG SR/FDC/VACCINES (RULE 122 E) DRUG SUBSTANCE(API)
DRUG PRODUCT(FORMULATION)
NOT USED IN COUNTRY *
SR/FDC/VACCINES
USE < 4 YEARS
EFFICACY=???
SAFETY=???
11/12/2018

5. SCOPE OF SCHEDULE Y
Rule 122-A, 122-B, 122-D, 122-E under Drugs & Cosmetics Rules 1945 in 1988/2000/2001/2002/2005
DRUG SUBSTANCE
DRUG PRODUCT
DEVELOPMENT STUDIES /PRECLINICAL DATA
IMPORT FOR TESTING ANALYSIS & EXAMINATION
CLINICAL STUDIES/BE STUDIES
DECISIONS BASED ON BEST AVAILABLE SCIENTIFIC EVIDENCE
11/12/2018

6. SCOPE OF SCHEDULE Y HERBALS:INDIAN SYSTEM OF MEDICINE & HOMEOPATHY
:APPROVAL BY STATE DRUG CONTROLLER
BIOTECHNOLOGY PRODUCTS:RECOMBINANT PRODUCTS:
DCGI
DBT
RDAC
DCGI=DRUG CONTROLLER GENERAL OF INDIA
DBT=DEPARTMENT OF BIOTECHNOLOGY
GEAC=GENETIC ENGINEERING APPROVAL COMMITTEEmanipulation of life forms at the genetic level through genetic engineering (and at the atomic level when combined with nanotechnology).   The engineering of life is inherently linked to ecological and health risks. 
Review Committee of Genetic Manipulation (RCGM) in the Department of Biotechnology, and not from the Genetic Engineering Advisory Committee (GEAC).  Under the Environment (Protection) Act 1986, the GEAC is the only body that can grant permission for importing genetically engineered substances (seeds in the present case). Therefore the import of Bt gene into India was illegal
powerfully intrusive technology from an ethical perspective
RDAC=Recombinant DNA Advisory Committee
IBSC=Institutional Biosafety Committee
Gene therapy claims first cancer victim
ISIS has warned of this possibility, not only from gene therapy, but also from other exposures to transgenic DNA, as from GM food. The artificial GM constructs used are similar in both cases.
The French team that made news in 2000 treating children with severe combined immune deficiency (SCID) had to call a halt to the gene therapy trial. One of the ten children treated developed leukaemia.
RCGM
IBSC
GEAC
11/12/2018

7. Ethical Guidelines for Biomedical Research on Human Subjects ICMR 2000
STATEMENT
SPECIFIC PRINCIPLES
GENERAL PRINCIPLES
CLINICAL
EVALUATION
DRUGS
DEVICES
HERBALS
VACCINES
EPIDEMIOLOGICAL STUDIES
GENETICS RESEARCH
TRANSPLANTATION INCLUDING FOETAL TISSUE TRANSPLANTATION
ASSISTED REPRODUCTIVE TECHNOLOGIES
PURPOSE
CONDUCT
EVALUATION
SCID is attributed to a mutation in a gene on the X-chromosome. Alain Fischer and Marina Cavezzena-Calvo at the Necker Hospital in Paris pioneered the ex vivo procedure, in which bone marrow cells taken from the patient are transformed outside the body, using a vector carrying a normal copy of the mutated gene to insert the gene into the genome. The transgenic cells are then re-introduced into the patient.
This was hailed as a breakthrough for gene therapy, as it avoided most of the risks of in vivo treatments in which the transgenes are directly introduced into the patient, which put patients at immediate risks from toxicities of the vector that killed teenager Gelsinger in In addition, infectious viruses could be generated from the vector, and cancer could result from the insertion of the vector into the wrong places in the genome. As in the genetic modification of plants and animals, the genetic modification of human beings is severely hampered, to a large extent, because precisely targeted gene insertion is still not technically feasible. It is hoped that by modifying the cells outside the patient’s body, the patient will not be directly exposed to high doses of the vector, and any cells that develop cancer, or any infectious viruses that are generated could be selected out.
But, a routine check of one patient last Spring revealed that the child had a high number of T cells in his blood, and by August, the T cell count reached cells per litre. The child was admitted to hospital.
Molecular analysis showed that the T cells were a clone derived from one original cell that has multiplied out of control. The retroviral vector used – mouse Moloney leukaemia virus – had jumped into a gene on chromosome 11 that is over-expressed in a form of acute leukaemia. An additional anomaly in these T cells was that part of chromosome 6 was duplicated and attached to chromosome 13. These are typical signs of transgenic instability.
It is a difficult choice when one is faced with a life-threatening condition that appears to be successfully treated by a procedure that so far, seems to carry a risk small enough to be worth taking.
But farm workers and members of the general public, who are not suffering from life-threatening conditions, are nevertheless exposed to the potential risks of transgenic DNA from eating GM foods and from other sources such as GM pollen.
We need is a comprehensive review not just of gene therapy, but also of other transgenic technologies that expose people to transgenic DNA, such as genetic modification of animals and plants for other biomedical and agricultural applications. The methods and constructs used are similar, and so are the risks involved.
11/12/2018

8. SPECIFIC GUIDELINES
Guidelines by DBT under DST: Biotechnology Products (Preclinical, clinical data for r-DNA based vaccines; diagnostics and other biological products
DCGI guidelines :BA/BE Studies
DCGI guidelines: Pharmacovigilance
Sources:
Science, News of the Week, 4 October 2002.
"What to do when clear success comes with an unclear risk?" Science 2002, 298,
"Predicted hazard of gene therapy a reality" ISIS Report, October 2002
11/12/2018

9. NDA vs. ANDA Review Process
PROCESS OF NEW DRUG DEVELOPMENT IN INDIA
NDA vs. ANDA Review Process
Brand Name Drug NDA Requirements
Generic Drug ANDA Requirements 1
Chemistry √ 2.
Manufacturing 3
Controls 4.
Labeling 5.
Testing 6
Animal Studies
√ ?
Bioequivalence Studies 7
Clinical Studies 8
Bioavailability Studies
11/12/2018

10. IMPLEMENTATION:SCHEDULE Y
Application Form 44 Submission
Rule
Rule 122 A
Rule 122 B
Rule 122 DA
Purpose:
Marketing Authorisation
Import
Manufacture
Clinical Study
Drug Substance
Form 45 A
Form 46 A
Drug Product
Form 45
Form 46
Application Form 12 Submission
Purpose
Import For Examination, Test and Analysis
Form 11
11/12/2018

11. DOCUMENT SUBMISSION TO DCGI IN ADDITION TO FORM 44
PROTOCOL
CASE REPORT FORMS
PRODUCT INFORMATION (Appendix I,II,III)
INVESTIGATOR UNDERTAKING [Appendix IV)
IEC APPROVAL [Appendix V] [Amendments/approvals]
INFORMED CONSENT FORMS(TRANSLATIONS): [Appendix VI ]
MARKETING /REGULATORY STATUS IN OTHER COUNTRIES
11/12/2018

12. Which studies ? When ?
Phase I
Phase II
Phase III
Product Already approved/
marketed in another country √
Product neither approved/ nor marketed in another country but phase III /II studies are in progress
√ if phase II
Studies
Are over
√ if phase III
Therapeutic confirmatory studies
Trials are generally allowed to be initiated at one phase earlier to the phase of trials in other countries
11/12/2018

13. Which studies ? When ? Phase I For new drug substances
discovered in other countries
Phase I trials are not usually allowed to be initiated in India unless Phase I data from other countries are available. Exception will be if product is of special relevance to the health problem of India.
discovered in India
√ Allowed in stages
11/12/2018

14. Post Marketing Surveillance
Which studies ? When ?
Phase IV
Post Marketing Surveillance
Periodic Safety Update Reports
Mandatory
Unexpected SAE
14 days
Other investigators
11/12/2018

15. ENSURE QUALITY:STABILITY STUDIES
STORAGE CONDITIONS
LONG
ACCELERATED
GENERAL
TEMPERATURE
30±2°c
40 ±2°c RH
65 ± 5%
75 ± 5%
MONTHS 12 06
REFRIGERATOR
5 ±3°c
25 ±2°c
60 ± 5%
FREEZER
-20 ±5°c
11/12/2018

16. RESPONSIVE IEC COMPOSITION FUNCTION DOCUMENTATION APPROVAL
REVISED SCHEDULE Y(2005):PROTOCOL BASED ON INDIAN GCP(2002) & ICMR ETHICAL GUIDELINES(2000)
SPONSOR
INDIAN GCP
SCIENTIFIC
IEC
GCP
Investigator:Training,undertaking,SOPs,consent checklist,unexpected SAE within 7 days to EC
Sponsor:IB+Protocol+SM+IP(Study manual and investigational product supply)
IEC:composition;function(SOPs are mandatory);documentation;approvals
GLP lab data
Human Subject:Consent+Confidentiality+Vulnerability
INVESTIGATOR
HUMAN SUBJECT
ETHICAL
ICMR GUIDELINES
11/12/2018

17. EXPERIMENTAL BIOEQUIVALENCE ELECTIVE CLINICAL PRACTICE NON ELECTIVE
NON THERAPEUTIC
THERAPEUTIC
EXPERIMENTAL
BIOEQUIVALENCE
ELECTIVE
CLINICAL
PRACTICE
NON ELECTIVE
Operations on donors for live donor organ transplants, aesthetic surgery, and non-therapeutic sterilization
RESEARCH
NON-
RESEARCH
(1) therapeutic non-research; (That is, "practice".) Within this category, one can distinguish two sub-categories: (a) elective therapy; (b) non-elective therapy; (2) therapeutic research; (3) non-therapeutic research; (This category includes research on healthy volunteer subjects.) and (4) non-therapeutic non-research. (This includes operations on donors for live donor organ transplants, aesthetic surgery, and non-therapeutic sterilization.) Neonatal circumcisionElective/Non-Elective With respect to designating a medical intervention as elective or non-elective, in one sense, all medical interventions to which informed consent is obtained are elective. However, the courts seem to use this term to indicate the degree of therapeutic necessity for undertaking the particular procedure. It is not easy to determine exactly how electiveness is being judged, but when it is not a clear-cut therapeutic decision that the patient should have undergone any given procedure or when, perhaps, the procedure might benefit the patient but failure to undergo it will not harm him or her (1), the procedure will be described as elective. (...) Research/Non-research ...[I]n the area of "proxy" consent, or as it is better called, third-party authorization, as the law presently stands, it is not possible for a guardian (or curator) to consent to a non-therapeutic research intervention on an incompetent person in his or her care. In contrast, guardians (or curators) may consent to some therapeutic research interventions on such persons. (...) Classification system ...it must be brought home to the patient that the intervention is non-therapeutic, if this is the case. Special care is needed in ensuring that there is apparent understanding of such information because patients tend to identify physicians with therapy and find it hard to believe that a physician would carry out a non-therapeutic procedure on them, even when they are expressly informed of this fact. (...) Finally, there are the non-therapeutic/non-research medical interventions. These include operations on live donors who give organs for transplant, non-therapeutic sterilization, and aesthetic or cosmetic surgery. Some aesthetic surgery may be classified as therapeutic when there is a definite psychological indication for undertaking it and, of course, some may even be physically therapeutic, although in such cases it would probably be labelled aesthetic surgery. Several Canadian cases have dealt with aesthetic surgery, but of those that preceded the Supreme Court's decision in Reibl v. Hughes, some, with all respect, are not clear as to the required scope of disclosure of information to the patient. In general, one can say that a very full disclosure is needed when non-therapeutic medical intervention is involved. More than one court has indicated expressly that, far from worrying about frightening a patient by too detailed a disclosure, a physician would have been well advised to frighten the patient into not requesting or deciding against a certain procedure (14). One of the difficulties raised by non-therapeutic/non-research medical intervention is whether it is legal or illegal. Although the latter used to be the commonly held view, in all probability there has been a change of public policy, which allows such intervention to be brought within the shelter of the law when certain conditions are fulfilled (15). (...) Incompetent persons When one moves outside the competent adult model, then whether a medical intervention is therapeutic or non-therapeutic becomes most important....It must always be kept in mind that more care is needed in giving permission for an intervention on another person than when we consent to have something done to ourselves. Finally, there is doubt as to whether third party authorization can be given to a non-therapeutic/non-research intervention; (...) Conclusion ... [W]hether therapy or non-therapy, and research or non-research is involved may alter the scope of the information that needs to be given to the patient to obtain his informed consent, and may make one aware of problems with voluntariness; that is, the presence of coercion. Such classification will also determine whether a guardian may authorize an intervention on his or her ward. (...) Notes: (1) Miller, B.L., "Autonomy and the Refusal of Life Saving Treatment" (1981), The Hastings Center Report 11(4)22, p. 27.
(14) See, for example, Kelly v. Hazlett (1977), 75 D.L.R. (3d) 536 (Ont. S.C.).
(15) See Somerville, M.A., Medical Interventions and the Criminal Law: Lawful or Excusable Wounding?" (1980), 26 McGill Law Journal (1) 82.
11/12/2018

18. Investigator Sponsor Human Subject CV IB Advertisement Protocol ICF
Before CONSIDERING the study :IEC SHOULD OBTAIN
Investigator
Sponsor
Human Subject CV IB
Advertisement
Protocol
ICF
Updates
Compensation
(1) therapeutic non-research; (That is, "practice".) Within this category, one can distinguish two sub-categories: (a) elective therapy; (b) non-elective therapy; (2) therapeutic research; (3) non-therapeutic research; (This category includes research on healthy volunteer subjects.) and (4) non-therapeutic non-research. (This includes operations on donors for live donor organ transplants, aesthetic surgery, and non-therapeutic sterilization.) Neonatal circumcisionElective/Non-Elective With respect to designating a medical intervention as elective or non-elective, in one sense, all medical interventions to which informed consent is obtained are elective. However, the courts seem to use this term to indicate the degree of therapeutic necessity for undertaking the particular procedure. It is not easy to determine exactly how electiveness is being judged, but when it is not a clear-cut therapeutic decision that the patient should have undergone any given procedure or when, perhaps, the procedure might benefit the patient but failure to undergo it will not harm him or her (1), the procedure will be described as elective. (...) Research/Non-research ...[I]n the area of "proxy" consent, or as it is better called, third-party authorization, as the law presently stands, it is not possible for a guardian (or curator) to consent to a non-therapeutic research intervention on an incompetent person in his or her care. In contrast, guardians (or curators) may consent to some therapeutic research interventions on such persons. (...) Classification system ...it must be brought home to the patient that the intervention is non-therapeutic, if this is the case. Special care is needed in ensuring that there is apparent understanding of such information because patients tend to identify physicians with therapy and find it hard to believe that a physician would carry out a non-therapeutic procedure on them, even when they are expressly informed of this fact. (...) Finally, there are the non-therapeutic/non-research medical interventions. These include operations on live donors who give organs for transplant, non-therapeutic sterilization, and aesthetic or cosmetic surgery. Some aesthetic surgery may be classified as therapeutic when there is a definite psychological indication for undertaking it and, of course, some may even be physically therapeutic, although in such cases it would probably be labelled aesthetic surgery. Several Canadian cases have dealt with aesthetic surgery, but of those that preceded the Supreme Court's decision in Reibl v. Hughes, some, with all respect, are not clear as to the required scope of disclosure of information to the patient. In general, one can say that a very full disclosure is needed when non-therapeutic medical intervention is involved. More than one court has indicated expressly that, far from worrying about frightening a patient by too detailed a disclosure, a physician would have been well advised to frighten the patient into not requesting or deciding against a certain procedure (14). One of the difficulties raised by non-therapeutic/non-research medical intervention is whether it is legal or illegal. Although the latter used to be the commonly held view, in all probability there has been a change of public policy, which allows such intervention to be brought within the shelter of the law when certain conditions are fulfilled (15). (...) Incompetent persons When one moves outside the competent adult model, then whether a medical intervention is therapeutic or non-therapeutic becomes most important....It must always be kept in mind that more care is needed in giving permission for an intervention on another person than when we consent to have something done to ourselves. Finally, there is doubt as to whether third party authorization can be given to a non-therapeutic/non-research intervention; (...) Conclusion ... [W]hether therapy or non-therapy, and research or non-research is involved may alter the scope of the information that needs to be given to the patient to obtain his informed consent, and may make one aware of problems with voluntariness; that is, the presence of coercion. Such classification will also determine whether a guardian may authorize an intervention on his or her ward. (...) Notes: (1) Miller, B.L., "Autonomy and the Refusal of Life Saving Treatment" (1981), The Hastings Center Report 11(4)22, p. 27.
(14) See, for example, Kelly v. Hazlett (1977), 75 D.L.R. (3d) 536 (Ont. S.C.).
(15) See Somerville, M.A., Medical Interventions and the Criminal Law: Lawful or Excusable Wounding?" (1980), 26 McGill Law Journal (1) 82.
11/12/2018

19. IEC :HOW IT SHOULD FUNCTION LIST MEMBERS SOPS PROCEDURE SCHEDULE
WHILE CONSIDERING the study :
IEC :HOW IT SHOULD FUNCTION
LIST MEMBERS
SOPS
PROCEDURE
SCHEDULE
& NOTIFY
INVESTIGATOR
REVIEW
QUORUM
NON MEMBER
INITIAL
CONTINUOUS
FINAL
VOTING
(1) therapeutic non-research; (That is, "practice".) Within this category, one can distinguish two sub-categories: (a) elective therapy; (b) non-elective therapy; (2) therapeutic research; (3) non-therapeutic research; (This category includes research on healthy volunteer subjects.) and (4) non-therapeutic non-research. (This includes operations on donors for live donor organ transplants, aesthetic surgery, and non-therapeutic sterilization.) Neonatal circumcisionElective/Non-Elective With respect to designating a medical intervention as elective or non-elective, in one sense, all medical interventions to which informed consent is obtained are elective. However, the courts seem to use this term to indicate the degree of therapeutic necessity for undertaking the particular procedure. It is not easy to determine exactly how electiveness is being judged, but when it is not a clear-cut therapeutic decision that the patient should have undergone any given procedure or when, perhaps, the procedure might benefit the patient but failure to undergo it will not harm him or her (1), the procedure will be described as elective. (...) Research/Non-research ...[I]n the area of "proxy" consent, or as it is better called, third-party authorization, as the law presently stands, it is not possible for a guardian (or curator) to consent to a non-therapeutic research intervention on an incompetent person in his or her care. In contrast, guardians (or curators) may consent to some therapeutic research interventions on such persons. (...) Classification system ...it must be brought home to the patient that the intervention is non-therapeutic, if this is the case. Special care is needed in ensuring that there is apparent understanding of such information because patients tend to identify physicians with therapy and find it hard to believe that a physician would carry out a non-therapeutic procedure on them, even when they are expressly informed of this fact. (...) Finally, there are the non-therapeutic/non-research medical interventions. These include operations on live donors who give organs for transplant, non-therapeutic sterilization, and aesthetic or cosmetic surgery. Some aesthetic surgery may be classified as therapeutic when there is a definite psychological indication for undertaking it and, of course, some may even be physically therapeutic, although in such cases it would probably be labelled aesthetic surgery. Several Canadian cases have dealt with aesthetic surgery, but of those that preceded the Supreme Court's decision in Reibl v. Hughes, some, with all respect, are not clear as to the required scope of disclosure of information to the patient. In general, one can say that a very full disclosure is needed when non-therapeutic medical intervention is involved. More than one court has indicated expressly that, far from worrying about frightening a patient by too detailed a disclosure, a physician would have been well advised to frighten the patient into not requesting or deciding against a certain procedure (14). One of the difficulties raised by non-therapeutic/non-research medical intervention is whether it is legal or illegal. Although the latter used to be the commonly held view, in all probability there has been a change of public policy, which allows such intervention to be brought within the shelter of the law when certain conditions are fulfilled (15). (...) Incompetent persons When one moves outside the competent adult model, then whether a medical intervention is therapeutic or non-therapeutic becomes most important....It must always be kept in mind that more care is needed in giving permission for an intervention on another person than when we consent to have something done to ourselves. Finally, there is doubt as to whether third party authorization can be given to a non-therapeutic/non-research intervention; (...) Conclusion ... [W]hether therapy or non-therapy, and research or non-research is involved may alter the scope of the information that needs to be given to the patient to obtain his informed consent, and may make one aware of problems with voluntariness; that is, the presence of coercion. Such classification will also determine whether a guardian may authorize an intervention on his or her ward. (...) Notes: (1) Miller, B.L., "Autonomy and the Refusal of Life Saving Treatment" (1981), The Hastings Center Report 11(4)22, p. 27.
(14) See, for example, Kelly v. Hazlett (1977), 75 D.L.R. (3d) 536 (Ont. S.C.).
(15) See Somerville, M.A., Medical Interventions and the Criminal Law: Lawful or Excusable Wounding?" (1980), 26 McGill Law Journal (1) 82.
11/12/2018

20. IEC :HOW IT SHOULD COMMUNICATE
AFTER CONSIDERING the study :
IEC :HOW IT SHOULD COMMUNICATE
APPROVAL OR FAVOURABLE OPINION
NOTIFY
MODIFICATIONS REQUIRED PRIOR TO APPROVAL
PROVIDE REASONS
PROCEDURES FOR APPEAL
UNFAVORABLE OPINION
TERMINATION OR SUSPENSION OF PRIOR APPROVAL
(1) therapeutic non-research; (That is, "practice".) Within this category, one can distinguish two sub-categories: (a) elective therapy; (b) non-elective therapy; (2) therapeutic research; (3) non-therapeutic research; (This category includes research on healthy volunteer subjects.) and (4) non-therapeutic non-research. (This includes operations on donors for live donor organ transplants, aesthetic surgery, and non-therapeutic sterilization.) Neonatal circumcisionElective/Non-Elective With respect to designating a medical intervention as elective or non-elective, in one sense, all medical interventions to which informed consent is obtained are elective. However, the courts seem to use this term to indicate the degree of therapeutic necessity for undertaking the particular procedure. It is not easy to determine exactly how electiveness is being judged, but when it is not a clear-cut therapeutic decision that the patient should have undergone any given procedure or when, perhaps, the procedure might benefit the patient but failure to undergo it will not harm him or her (1), the procedure will be described as elective. (...) Research/Non-research ...[I]n the area of "proxy" consent, or as it is better called, third-party authorization, as the law presently stands, it is not possible for a guardian (or curator) to consent to a non-therapeutic research intervention on an incompetent person in his or her care. In contrast, guardians (or curators) may consent to some therapeutic research interventions on such persons. (...) Classification system ...it must be brought home to the patient that the intervention is non-therapeutic, if this is the case. Special care is needed in ensuring that there is apparent understanding of such information because patients tend to identify physicians with therapy and find it hard to believe that a physician would carry out a non-therapeutic procedure on them, even when they are expressly informed of this fact. (...) Finally, there are the non-therapeutic/non-research medical interventions. These include operations on live donors who give organs for transplant, non-therapeutic sterilization, and aesthetic or cosmetic surgery. Some aesthetic surgery may be classified as therapeutic when there is a definite psychological indication for undertaking it and, of course, some may even be physically therapeutic, although in such cases it would probably be labelled aesthetic surgery. Several Canadian cases have dealt with aesthetic surgery, but of those that preceded the Supreme Court's decision in Reibl v. Hughes, some, with all respect, are not clear as to the required scope of disclosure of information to the patient. In general, one can say that a very full disclosure is needed when non-therapeutic medical intervention is involved. More than one court has indicated expressly that, far from worrying about frightening a patient by too detailed a disclosure, a physician would have been well advised to frighten the patient into not requesting or deciding against a certain procedure (14). One of the difficulties raised by non-therapeutic/non-research medical intervention is whether it is legal or illegal. Although the latter used to be the commonly held view, in all probability there has been a change of public policy, which allows such intervention to be brought within the shelter of the law when certain conditions are fulfilled (15). (...) Incompetent persons When one moves outside the competent adult model, then whether a medical intervention is therapeutic or non-therapeutic becomes most important....It must always be kept in mind that more care is needed in giving permission for an intervention on another person than when we consent to have something done to ourselves. Finally, there is doubt as to whether third party authorization can be given to a non-therapeutic/non-research intervention; (...) Conclusion ... [W]hether therapy or non-therapy, and research or non-research is involved may alter the scope of the information that needs to be given to the patient to obtain his informed consent, and may make one aware of problems with voluntariness; that is, the presence of coercion. Such classification will also determine whether a guardian may authorize an intervention on his or her ward. (...) Notes: (1) Miller, B.L., "Autonomy and the Refusal of Life Saving Treatment" (1981), The Hastings Center Report 11(4)22, p. 27.
(14) See, for example, Kelly v. Hazlett (1977), 75 D.L.R. (3d) 536 (Ont. S.C.).
(15) See Somerville, M.A., Medical Interventions and the Criminal Law: Lawful or Excusable Wounding?" (1980), 26 McGill Law Journal (1) 82.
11/12/2018

21. Adverse Drug Reaction (ADR)
All noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions. The phrase responses to a medicinal product means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility, i.e. the relationship cannot be ruled out.
Response to:Casual relationship is a reasonable possoibility
Dose:Any dose if product is at preapproval stage /or when therapeutic dose has not been established
Regarding marketed medicinal products: a response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis,diagnosis, or therapy of diseases or for modification of physiological function
11/12/2018

22. Adverse Event (AE)
Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event (AE) can therefore be any
unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product
11/12/2018

23. REPORT IMMEDIATELY Serious adverse event (SAE)
Any adverse experience occurring that results in any of the following outcomes
Death (irrespective of initial impression of causality)
REPORT IMMEDIATELY
Life-threatening
Hospitalization or prolongation of existing hospitalization
A persistent or significant disability/incapacity
A congenital anomaly or birth defect.
Reporting of Unexpected Serious Adverse Events
The sponsor should promptly report all adverse drug reactions (ADRs) that are both serious and unexpected
Sponsor should promptly report findings that adversely affect the safety of the subjects, impact trial conduct or alter favorable opinion of IRB
Reporting should be to all investigators/institutions, IRBs, applicable regulatory agencies
11/12/2018

24. SAE/AR Reporting
Related to or associated with the use of the investigational product
There is a reasonable possibility that the event was caused by the investigational product.
Reasonable: Temporal Relationship
Known Pattern
Reporting of Unexpected Serious Adverse Events
The sponsor should promptly report all adverse drug reactions (ADRs) that are both serious and unexpected
Sponsor should promptly report findings that adversely affect the safety of the subjects, impact trial conduct or alter favorable opinion of IRB
Reporting should be to all investigators/institutions, IRBs, applicable regulatory agencies
11/12/2018

25. UNEXPECTED SAE Expected/unexpected/unanticipated
An expected event is one where the specificity and severity of the event are consistent with the information in the investigator brochure, labeling for the product, or contained else where in the investigational plan. Unexpected events are all other occurrences.
Reporting of Unexpected Serious Adverse Events
The sponsor should promptly report all adverse drug reactions (ADRs) that are both serious and unexpected
Sponsor should promptly report findings that adversely affect the safety of the subjects, impact trial conduct or alter favorable opinion of IRB
Reporting should be to all investigators/institutions, IRBs, applicable regulatory agencies
11/12/2018

26. FUTURE DIRECTION: PRDC (1999) Recommendations on CDSCO
PROTOCOL :ADVISORY BOARD
FULL TIME EXPERTS/EXPERT PANELS
TIME SCHEDULE FOR DRUG APPROVAL
* IND PHASE I :WITH IN 3 MONTHS
* IND PHASE II:WITHIN 6 MONTHS
* MARKETING APPROVAL:3 MONTHS
At present what is needed is EXPERTISE +DATA ANALYSIS +TIME TO MANAGE RISK BY ANALYSING THE TOTAL PROCESS RATHER THAN THE END PRODUCT.
Students in the UK (most of whom are in dire financial straits following withdrawal of government support) were offered £600 to take highly toxic organophosphate pesticides normally tested on rats. The university at which the experiments took place were no doubt offered suitable financial incentives to see no evil, hear no evil. Organophosphates (related to nerve agents) are known to cause brain damage and may be a factor in Gulf War Syndrome. The advantages to the pesticide company conducting the tests is that they hope to use the results to argue for a tenfold increase in permitted pesticide residues
Pharmaceutical Research & Development Committee (PRDC)
11/12/2018

27. FUTURE DIRECTION: REGULATOR INVESTIGATOR SPONSOR RISK MANAGEMENT
ACCESSIBILITY
IEC
HUMAN SUBJECT
11/12/2018

28. Thank You
11/12/2018