International Institute of Medicine and Science, Inc. 
Dedicated to the Preservation and Betterment of  Human Lives Through Advanced Medical Sciences Research, Education, and Service to the Communities we Serve and Humanity 
A Member of the World Association of Non-Governmental Organizations (WANGO)              
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Programs-Education
        Several educational programs are carried out at the International Institute for Medicine and Science, Inc. for medical residents, physician-scientists, and medical  and biomedical scientists. Courses are permanently available and can be offered in different venues upon arrangement with the Institute. Syllabi are provided below:         

        Course # 1: "Scientific Research Methodology"*         
        Course Director: Dr. Alain L. Fymat          

        This project is a three-part course, which teaches medical residents and physician-scientists the scientific method, the medical methodologic standards, and the probabilistic measure of diagnostic tests.   

        Part 1: THE SCIENTIFIC METHOD                 

        (A) Selecting and Stating a Research Problem: 
                    Choose an I.C.N. Research Problem (I=Interest, C=Connectivity, N= Newness); and 
                    State the Problem the B.R.E. Way (B=Background, R= Restatement, E= Examination
         
        (B) Literature Search: 
                    Structure of the Scientific and Medical Literature; and 
                    Approaches to Search(es)
         
        (C) The Scientific Method: 
                    The Seven Pairs of the Scientific Method: 
                            Observation & Description; 
                            Cause & Effect; 
                            Analysis & Synthesis; 
                            Hypothesis & Law of Nature; 
                            Induction & Deduction; 
                            Necessary & Sufficient Condition; and 
                            Models & Mathematics 
                    The Search for Causes: 
                            Method of Agreement; 
                            Method of Differences; 
                            Combined Method of Agreement and Differences; 
                            Method of Concomitant Variations         

        (D) Design and Experiment:  
                    First Principles: 
                            Basic Understanding of the Problem and its Theory; 
                            One or more Hypotheses for the Experiment; 
                            Analyze and Simplify the Problem; 
                            Some Problems Can be Answered only by Direct Experimentation; and 
                            The Crucial Experiment
                    Planning the Experiment: 
                            Decision Process; 
                            Variables Selection; 
                            Measurement Attribute (Absolute, Relative); 
                            Classification, Sampling and Measurement; 
                            Controls and Standards: Biases; and Replication                                    

        (E) Designing an Apparatus          

        (F) Executing an Experiment         

        (G) Analyzing Experimental Data: 
                    Systematic and Random Errors; 
                            Mean and Standard Deviation; 
                            Distributions: Binomial; Poisson; Gaussian (or Normal Error Distribution); and 
                            Lorenzian 
                    Estimates of Mean and Errors: 
                            Method of Least Squares; 
                            Instrumental Uncertainties; 
                            Statistical Fluctuations; and 
                            Chi-Square Test of Distribution 
                    Propagation of Errors
                    Correlation Probability
                    Multiple Linear and Non-Linear Regressions
                    Goodness of Fit
                    Fitting Composite Curves and Arbitrary Functions
                    Data Manipulation: 
                            Smoothing; 
                            Interpolation & Extrapolation; and 
                            Area Integration.         

        (H) Errors of Measurement        

        (I) Probability, Randomness & Logic           

        (J) Mathematical Work          

        (K) Numerical Computations         

        (L) Reporting Research Results 

        Part 2: MEDICAL METHODOLOGIC  STANDARDS          

        (A) For Technical Capacity Studies         

        (B) For Diagnostic Accuracy Studies          

        (C) For Diagnostic Impact Studies         

        (D) For Therapeutic Impact Studies          

        
(E) For Patient Outcome Studies 

        Part 3: PROBABILISTIC MEASURE OF DIAGNOSTIC TESTS         

        
(A) Clinical Decisions Without Definitive Information          

        (B) The Treatment Threshold Model of Decision Making          

        (C) Probability Theory in the Use of Diagnostic Tests: 

                    The Four Principles: 
                            "Probability is a Useful Representation of Diagnostic Accuracy"; 
                            "Diagnostic Tests Should be Obtained Only When They Can Alter Case Management;
                            "Effects of Test Results on Clinical Outcomes are Little Known"; and 
                            "Test Performance (Cost v. Incremental Benefit to Patient) is Little Known" 
                    The Post-Test Probability of Disease Depends on Three Factors: 
                            Pre-Test Probability; 
                            Sensitivity; and Specificity
                    Bayes' Theorem Utility: 
                            Calculates the Post-Test Probability of Disease; and 
                            Facilitates Test Results Interpretation. 
                    Pre-Test Probability Utility: 
                            Affects Probability that a Test Result Will Occur; 
                            Is an Important Factor in Predicting the Effect of a Given Diagnostic Test on Case Management; and
                            Is Influenced by Experience
                    Sensitivity and Specificity Attributes:         
                            Sensitivity and Specificity are Opposites;                             
                            Sensitivity and Specificity Measurements are Important but Difficult; and     
                            Contribute to Determine Post-Test Probability

* This course was taught by ALF at the Loma Linda University, School of Medicine, Loma Linda, California to Radiology Residents and at the U.S. Department of Veterans Affairs, Loma Linda Medical Center, Loma Linda, California to Radiology Residents and physicians-scientists.         


        Course # 2: " Clinical Drug Development Trial Phases" *         
        Course Director: Dr. Alain L. Fymat         

        
This course reviews the process involved in clinical trial phases. It is addressed to medical researchers, and to pharmaceutical company sponsors and their contractors who plan to be involved in human clinical trials. The course covers the drug discovery process and the various phases of a clinical trial.         

        REGULATORY DEFINITIONS:        

        (A) Investigational New Drug (IND): 
        Federal Regulation 21 CFR 312: A new drug or biological drug used in a clinical investigation. Also includes a biological product used in vitro for diagnostic purposes. 
        Veterans Health Administration (VHA) Regulation M2, Pt VII, Ch 6: Medication for which a NEW DRUG APPLICATION (NDA) has been filed with the FDA. It may be a new chemical compound not released by the FDA for general use. Or, it may be an approved drug used for an unapproved or approved use in a controlled, randomized, or blinded clinical trial. Usually not available through commercial channels         

        (B) Treatment and Use: (Not for humanitarian use) 
        VHA Regulation M2, Pt VII, Ch 6: Investigational drug granted FDA approval to be used by a qualified investigator in patients with a serious or life-threatening illness. There is a nationally-approved treatment protocol for which the patient must be eligible and have a specific treatment plan. Sponsor may charge the subject for the drug; therefore local policies regarding these drugs must be established.   

        Part 1: THE DRUG DISCOVERY PROCESS: 
                    
        VHA Regulation: Before a pharmaceutical company begins testing a drug in humans, it does extensive laboratory and animal testing. The pre-clinical testing provides an understanding of the drug's biological activity, toxicity, half-life and some indication of its potential side effects. To begin human testing, the company must present this pre-clinical data to the FDA and detail its plan for clinical trials (IND Application). All trials are conducted with the: Tacit approval of the FDA, and the Active approval of the IRB. The IRB is the moral and ethical watchdog of the clinical trial process. No trial can be concluded without the supervision of the IRB. 

        Part 2: TRIAL PHASES         

        (A) PHASE 1: 
                    Primary concern: Assessing drug safety: Population: 20-80 healthy young volunteers 
                            (Note: In oncology studies, the number of subjects depends on toxicity and dose escalation); 
                    Procedures: Subjects confined to a dedicated Phase 1 unit (or outpatient facility for vaccine studies);         
                    Serum drug levels/chemical profiles are drawn every hour for 24 hours; 
                    Subjects are closely monitored. 
                    Products: 
                            Drug absorption, metabolism and excretion; 
                            Mechanisms of action in humans; 
                            Side effects with increasing doses; 
                            Evidence on effectiveness. Success rate: 70% successful completion of Phase 1.          

        (B) PHASE 2: (A- Early phase; B= Late phase) 
                    Primary concern: Drug safety 
                    Secondary concern: Drug efficacy 
                    Gold standard: Double-blind, placebo-controlled trial. 
                            (Note: Placebo is not used in oncology studies.) 
                    Population: ~ Several 100's. 
                    Products: 
                            Drug safety; 
                            Preliminary efficacy; 
                            Side effects profile; Associated risks.           

        (C) PHASE 3: (A=Early Phase; B=Late Phase) 
                    "Pivotal trials": Critical to NDA application
                    Other concomitant trials: In 30-100 centers across the U.S. or in other countries, either part of the 
                    original plan or to answer Phase 2 questions
                    Primary concern: 
                            Efficacy
                            Population: Several 100's to several 1,000's
                            Full spectrum: men, women, children, elderly, diverse ethnic groups
                            Products: 
                                    Additional information about safety and effectiveness for overall benefit/risk; 
                                    Adequate basis for physician labeling: NDA submitted to FDA for approval; 
                                    Begin Phase 3B. (D) 

        (D) PHASE 4: 
                    Purpose: Bridge gap between research and marketing
                    Reason: More commonly requested by FDA because it takes large numbers of doses to understand the 
                    potential side effects of a drug

* This course was taught by ALF to the medical staff and contractors of the U.S. Department of Veterans Affairs, Veterans Health Administration (VHA), Office of Research Oversight (ORO) in the context of their regulatory oversight of clinical trials conducted within VHA. 


        Course # 3: "Clinical Trials: Investigators' Responsibilities" 
        
Course Director: Dr. Alain L. Fymat 

        This course reviews the investigators' responsibilities throughout the clinical drug development process. It is addressed to physician-scientists and their collaborators who are or plan to be involved in human clinical trials. 

        Part 1: SUMMARY OF REGULATORY RESPONSIBILITIES 
                    
                    In VHA Handbook 1200.5 para 14: "Investigational Drugs in Research with Human Subjects"; 
                    In filing Form FDA 1572 (verso) [21 CFR 312.53(c)]; 
                    In conducting study (ICH GCP Guidelines); 
                    In record development, maintenance, and retention; 
                    In 21 CFR 54 (Financial Disclosure); 
                    In 21 CFR 312, Subpart D ("Responsibilities of Sponsors and Investigators")

        Part 2: FORM FDA 1572 para 9 ("Statement by Investigator): 

                    Conduct or supervise trial personally, according to approved Protocol; 
                    Only make changes in a Protocol after notifying the Sponsor (except when necessary to protect the 
                            safety, rights, or welfare of subjects); 
                    Inform patients or any persons used as controls that drugs are being used for investigational purposes, 
                            and obtain consent [21 CFR 50] and IRB review and approval [21 CFR 56]; 
                    Properly report to sponsor any Adverse Events (AEs) [21 CFR 312.64]; 
                    Read/understand investigator's Brochure, and be aware of potential risks and side effects of the drug; 
                    Be responsible for the investigating team; Maintain accurate records [21 CFR 312.62], make them 
                            available for inspection and copying [21 CFR 312.68]; 
                    Work under the direction of a qualified IRB [21 CFR 56]: 
                            Initial and continuing review; 
                            Approval of clinical investigation; 
                            Reports of changes in research activity and all unanticipated problems involving risks to human
                                    subjects or others; 
                            Approval of changes in the research (except where necessary to eliminate apparent immediate
                                    hazards to human subjects); 
                            Comply with all other requirements in [21 CFR 312, Subpart D: "Responsibilities of Sponsors and 
                                    Investigators")

        Part 3: ICH GCP GUIDELINES and FR May 9, 1997:Para 4.1: 

                    Qualifications and Agreements: 
                            Principal Investigator (PI) should: 
                                    Be qualified by education, training and experience, compliance with ICH GCP and applicable 
                                            regulatory requirements. Provide evidence of the same; 
                                    Be thoroughly familiar with appropriate use of IPs; 
                                    Permit monitoring and auditing by sponsor, and inspection by appropriate regulatory 
                                            authorities; 
                                    Maintain a list of qualified persons to whom he/she has delegated significant trial-related 
                                            duties       
                    Para 4.2: Adequate Resources: 
                            PI should: 
                                    Demonstrate potential for recruiting required number of suitable subjects within agreed
                                            recruitment period;         
                                    Have sufficient time to properly conduct and complete trial within the agreed trial period;
                     
                                    Have available an adequate number of qualified staff and adequate facilities for the foreseen 
                                            duration of the trial;         
                                    Ensure that all support personnel are adequately informed about the protocol, IPs, and their trial
                                            -related duties and functions

                    Para 4.3: Medical Care of Trial Subjects: 
                            Qualified PI/sub-investigator must: 
                                    Be responsible for all trial-related medical decisions; 
                                    Provide adequate medical care for any AEs, including significant laboratory values; 
                                    Inform subject's primary physician about subject's participation in trial (if subject agrees); 
                                    Make a reasonable effort to ascertain reasons(s) why subjects withdraw prematurely while fully 
                                            respecting the subject's rights

                    Para 4.4: Communication with IRB: 
                                 PI must: 
                                            Have written/dated IRB approval for trial protocol, written IC form and its updates, subject 
                                                    recruitment procedures and any other information to be provided to subject; 
                                            Provide the IRB a current copy of investigator's Brochure and any updated copies;     
                                            Provide the IRB all documents subject to its review

                    Para 4.5: Compliance with Protocol: PI should: 
                                Conduct trial according to approved Protocol, sign the Protocol (or alternative contract) to confirm
                                        his/her agreement; 
                                Not implement any deviation from/changes to the Protocol without agreement by the Sponsor and 
                                        prior IRB review/approval except where necessary to eliminate an immediate hazard to 
                                        subjects, or when changes involve only logistical/ administrative aspects of the trial; 
                                Document and explain any deviation(s) from the approved Protocol; Implement Protocol deviation 
                                        to eliminate an immediate hazard, even without prior IRB approval. Immediately thereafter, 
                                        submit to IRB review and to Sponsor for agreement, and to regulatory authorities. 

                    Para 4.6: Investigational Products (IPs): PI must: 
                                Account for IPs at the trial site(s); 
                                Where allowed/required, assign some/all PI's Institution duties to appropriate Pharmacist or other
                                        appropriate individual under PI's institution supervision; 
                                Maintain site records of product's delivery, inventory, use by each subject, return to the Sponsor or 
                                        alternative disposition of unused product(s); 
                                Records should include: dates, quantities, batch/serial numbers, expiration dates, unique code 
                                        numbers, doses delivered to subjects, reconciliation with all IPs received from the Sponsor; 
                            IPs should be stored as specified by the Sponsor and in accordance with regulatory requirements; 
                            IPs are used only in accordance with approved Protocol; 
                            PI/designate should explain to each subject the correct use of IPs, and should periodically check their 
                                        use.

                    Para 4.7: Randomization Procedures & Unblinding: PI should: 
                            Follow the trial's randomization procedures, if any; 
                            Ensure the code is broken only in accordance with the Protocol; 
                            Promptly document and explain to the Sponsor any premature unblinding , e.g., accidental
                                        unblinding, unblinding due to Serious Adverse Events (SAEs), etc. 

                    Para 4.8: Informed Consent (IC) of Trial Subjects: 

                    Para 4.9: Records & Reports (R&Rs): 
                            Data reported in Case Report Forms (CRFs) and in other reports are accurate, complete, legible and 
                                    timely; CRF data derived from source documents are consistent with source documents, or 
                                    discrepancies explained; Any change/correction to a CRF is dated, initialed, explained, and
                                    should not obscure the original entry; Investigator maintains record of changes and corrections; 
                            Financial aspects of the trial are documented in an agreement between sponsor and investigator; 
                            The "Essential Documents for the Conduct of a Clinical Trial" - see International Commission for
                                    Harmonization Good Clinical Practice (ICH GCP Guidelines, Section 8) are maintained, and 
                                    measures taken to prevent their accidental or premature destruction; 
                            Essential Documents are retained until at least 2 years after last approval of a marketing
                                    application, or at least 2 years after discontinuing the IP development. 
                            Documents should be retained for a longer period if regulatorily required; 
                            Upon request, all trial-related records are available to monitor, auditor, IRB.

                    Para 4.10: Progress Reports (PRs): 
                            Where required, PRs are submitted promptly and periodically (annually or more frequently) to the 
                                    IRB, the Institution and the Sponsor; 
                            Reports cover any changes significantly affecting the conduct of the trial and/or increasing the risk 
                                    to patients. 

                    Para 4.11: Safety Reporting: 
                            Immediate Reports: All SAEs (except those identified in the Investigator's brochure as not needing 
                                    immediate reporting); 
                            Follow-up Detailed reports: 
                                    Promptly follow immediate reports; 
                                    AEs and/or Laboratory Abnormalities: If identified in the Protocol as critical to safety
                                             evaluations; 
                                    Death Reports and other information (autopsy reports, terminal medical reports). 

                    Para 4.12: Premature Trial Termination or Suspension: 
                            Promptly inform trial subjects, assure appropriate therapy and follow-up and, where applicable, 
                                    inform regulatory authorities; 
                            If PI terminates/suspends trial without prior sponsor agreement: 
                                    PI should inform the Institution, Sponsor, IRB; 
                            If Sponsor terminates/suspends trial: 
                                    PI should promptly inform the Institution, IRB; 
                            If IRB terminates/suspends trial: 
                                    PI should inform the Institution, the PI/Institution, the Sponsor. 

                    Para 4.13: Final Reports (FRs): Investigator, Institution: 
                            Upon completion of the trial, the PI should: 
                                    Inform the Institution, and the Investigator/Institution, the Sponsor; 
                                    Provide the Sponsor with all required reports; 
                                    Provide the IRB a summary of trial's outcome; 
                                    Provide the regulatory authorities any reports they require.

* This course was taught by ALF to the medical staff and contractors of the U.S. Department of Veterans Affairs, Veterans Health Administration (VHA), Office of Research Oversight (ORO) in the context of their regulatory oversight of clinical trials conducted within VHA

        Course # 4: "Investigator Responsibilities for Records" 
        Course Director: Dr. Alain L. Fymat

                    Para 1: Study Binder: 
                            The binder shall contain: 
                                    Signed Protocol original and all amendments; 
                                    Original Forms: FDA 1572; VA 10-9012 (Investigational Drug Information record); 
                                    Updated/signed/dated CVs for all investigators (a good practice but see Notes a, b, c and d
                                            below); 
                                    Laboratory certifications and reference range for laboratory values (a good practice but see 
                                            Notes a and e); 
                                    Drug brochure and package inserts; IRB letter of approval; 
                                    IRB updates and notifications, including SAEs; 
                                    Original signed/stamped IRB-approved IC form; 
                                    All advertisements with IRB approvals; 
                                    Have copy of Office for Human Research Protection (OHRP) Assurance (includes Registration 
                                            number); 
                                    Study close-out or final report to IRB; 
                                    All study-related correspondence; 
                                    All drug receipts, records and inventories; 
                                    Telephone and screening logs. 
                    Notes
                                    a. Strictly speaking, not a regulatory requirement. Thus, see b and c below; 
                                    b. 21 CFR 312.53(a) requires "... select(ing) investigators qualified by training and experience as
                                             appropriate experts to investigate the drug"; 
                                    c. 21 CFR 312.53(c)(1)(viii) only requires "...a list of the names of the sub-investigators who will be
                                             assisting the investigator in the conduct of the investigations(s)" 
                                    d. 21 CFR 312.53(c)(2) states: "A curriculum vitae or other statement of qualifications of the 
                                             investigator showing the education, training and experience that qualifies then investigator
                                             as an expert in the clinical investigation of the drug for the use under investigation(s)"; 
                                    e. CFR 3(c)(1)(iv)312.521 requires "The name and address of any clinical laboratory facilities to be
                                             used in the study". 

            Para 2: Source Documents: 
                        Patient medical history; 
                        Physical examination results; 
                        Current modifications; 
                        Medications discontinued in the past 30 days; 
                        Note that IC has been signed; 
                        Telephone logs (a good practice but not a regulatory requirement); 
                        Appointment books; Screening logs (including "screen failure"); 
                        Note dated/signed by investigator describing each patient's every visit, completed procedures, 
                                treatments received, and SAEs; 
                        Coordinator's appointment book. Para 3: Case Report Forms (CRFs): Sponsor's CRF is designed to
                                assess drug safety and efficacy. 
                        Records must include: 
                                Accurate CRF for each enrollee, consistent with source documents, is the final "product" delivered 
                                        by the site to the Sponsor. 

            Para 4: Standard Operating Procedures (SOPs)

* This course was taught by ALF to the medical staff and contractors of the U.S. Department of Veterans Affairs, Veterans Health Administration (VHA), Office of Research Oversight (ORO) in the context of their regulatory oversight of clinical trials conducted within VHA. 

        Course # 5: "Investigator's Financial Disclosure Responsibilities" (21 CFR 54)* 
        Course Director: Dr. Alain L. Fymat

            Para 54.2: Definitions: Financial arrangements include: 
                    Compensation affected by the outcome of clinical studies: Compensation explicitly greater for a favorable
                            result or compensation in form of equity interest in Sponsor or royalty interest; 
                    Significant equity interest in the Sponsor or a covered study: Stock options or the like that exceed 
                            $50,000 during study and for 1 year after its completion; 
                    Proprietary interest in the tested product: Property or other financial interest (patent, trademark,
                            copyright, licensing agreement); 
                    Significant payments of other sorts made by Sponsor to investigator or more than $25,000 during the 
                            time of the study and 1 year thereafter. 

            Para 54.3: Scope: 
                    Applies to any applicant who submits a marketing application for a human drug, biologic product, or
                             device and who submits "covered clinical studies" (that is, any study of a drug or device submitted in
                             a marketing application or reclassification petition that the applicant or FDA relies on to establish
                             the product is effective;
                   Includes studies that show equivalence to an effective product, or any study in which an investigator
                             makes a significant contribution to the demonstration of safety). 

            Para 54.4: Certification of Disclosure: 
                   For each covered clinical study, applicant must submit: 
                             List of investigators including Sponsor's employees (full/part time) to determine whether applicant's
                                     product meets FDA's marketing requirements; 
                             Complete and accurate disclosure or certification of financial interests of clinical investigators who 
                                     are not full/part time sponsor employees; 
                             Clinical investigators subject to IND or IDE regulations must provide Sponsor with sufficient 
                                     information needed to allow subsequent disclosure or certification; 
                             Applicant must submit for each participating clinical investigator either a certification that none of 
                                     the defined financial arrangements exist or disclose the nature of arrangements; 
                             Certification: Form FDA 3454 dated/signed by CFO/other responsible corporate officer for all 
                                     covered studies or list the covered studies; 
                             Disclosure: Form FDA 3455 disclosing completely and accurately: 
                                    Any Sponsor/Investigator financial arrangements; 
                                    Any significant Sponsor payments (grant to fund ongoing research, compensation); 
                                    Any Investigator's proprietary interest; 
                                    Any Investigator's significant equity interest; 
                                    Any steps take to minimize potential bias from the disclosed arrangements. 

            Para 54.6: Record Keeping and retention: 
                    Record Keeping: 
                            Financial interests or arrangements for payments [54.4(a)(3)(i)]; 
                            Other significant payments (54.4(a)(3)(ii)]; 
                            Proprietary or significant equity interest in product [54.4(a)(3)(iii)]. 
                            Record retention: 2 years after approval date of application for the indication that was tested by the 
                                    Investigator; 
                            Upon FDA request, available for review/copying.

* This course was taught by ALF to the medical staff and contractors of the U.S. Department of Veterans Affairs, Veterans Health Administration (VHA), Office of Research Oversight (ORO) in the context of their regulatory oversight of clinical trials conducted within VHA. 

        Course # 6: "Clinical Trials: Institutional Review Board's Responsibilities"
        Course Director: Dr. Alain L. Fymat 

        This course reviews the Institutional Review Board (IRB) oversight responsibilities in the approval and oversight of clinical trials. It is addressed to IRB members and their consultants who are or plan to become involved in overseeing human clinical trials. The Syllabus is provided below.

* This course was taught by ALF to the medical staff and contractors of the U.S. Department of Veterans Affairs, Veterans Health Administration (VHA), Office of Research Oversight (ORO) in the context of their regulatory oversight of clinical trials conducted within VHA.
                                                                                                                                                                                                                             
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