Drug Development Process Lecture IV

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Drug Development Process Lecture IV
2013-12-03 18:07:58
Drug Development

Drug Development Process
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  1. IND

    • • The IND Application is a submission by which a drug sponsor alerts the FDA of its intention to conduct clinical studies with an investigational drug.
    • • The IND is legally required to conduct a clinical trial in the United States.
    • • IND Applications are NEVER APPROVED by FDA. Instead, sponsors are permitted to initiate the clinical trial(s) proposed in application 30 days after the agency receives the application. Start of clinical studies is CONTIGENT ON THE FDA NOT ISSUING A CLINICAL HOLD on the proposed study(ies) during the 30 day review period
    • • Commercial IND
    • – Submitted by biotech and pharmaceutical companies
    • – Not the most common type of IND Application

    • Investigator IND (also called Research IND)
    • – Submitted by physician who initiates and conducts the clinical trial
    • – Usually this IND is for clinical studies on a previously studied & approved drug for the purpose of:
    •     • An approved drug for a new indication
    •     • Publication of a research paper
    • Emergency Use IND (also called Compassionate Use or Single Patient IND)
    • – FDA authorizes immediate shipment of an Investigational drug for a desperate or life threatening medical situation. This IND application is not completed until AFTER the drug has been administered to the study subject.

    • Treatment IND (also called Expanded Drug Access IND)
    • – Experimental drug exhibiting promise in a clinical scenario for serious or life threatening diseases is made available to patients with the target disease while the final phases of clinical research are ongoing, i.e., BEFORE formal FDAapproval.
    • – (“Parallel Track”: makes investigational antiretroviral drugs available prior to FDA approval to AIDS/HIV patients who have no therapeutic alternatives and do not qualify to participate in clinical trials.)

    • “Screening IND”
    • – Not formally codified in 21 CFR & requires agreement with FDA prior to submission
    • – Comprises an IND through which a drug sponsor seeks permission in a single IND Application to test several closely related chemical entities in an initial clinical trial
    • – Employed when more than one drug candidate not discriminated based on nonclinical studies
    • – Once the lead drug candidate is established based on the clinical study detailed in this IND, the sponsoring pharmaceutical company must prepare a new IND Application for the one drug candidate the company intends to advance.
    • • Drugs intended solely for testing in vitro or in lab animals
    • • Clinical investigations in humans involving placebo entities
    • • Approved drugs if all of these criteria apply:
    • 1. Trial not intended to be reported to FDA to support a new indication nor to support a label change
    • 2. Trial not intended to support a change in advertising the drug
    • 3. The trial does not involve a route of administration or dosage change, or use in a population that significantly increases risks (i.e., generally an “off label” use for which no previous safety data exists)
    • 4. IRB review & approval and Informed Consent Form required
    • • Bioavailability and bioequivalence studies in humans using approved drugs (if the dosage tested is within the approved dosage range)
    • On average, in any given year, clinical holds are issued for approximately10% of initial IND submissions

    • • Common reasons for issuing a Clinical Hold
    • – Risks to human subjects are unreasonable and significant
    • – Investigators not qualified
    • – Investigator Brochure false or misleading
    • – Insufficient information to assess risk
    • – Gender exclusion for a conditions that occurs in both men and women
  5. Content of the IND Application
    • 1. Form FDA 1571 (entitled Investigational New Drug Application [IND])
    • 2. Table of Contents
    • 3. Introductory Statement
    • 4. General Investigational Plan
    • 5. Investigator’s Brochure
    • 6. Clinical Protocols (at least Phase I)
    • 7. Chemistry, Manufacturing, and Control (CMC) Data
    • 8. Non Clinical Pharmacology & Toxicology Data
    • 9. Previous Human Experience (if applicable)
    • 10. Additional Information (e.g., plans for pediatric studies)
    • 11. Biosimilar User Fee Cover Sheet
    • 12. Clinical Trials Certification of Compliance

    Form FDA 1571 (Main Elements)
    • – Sponsor & investigational drug identification
    • – Name of drug & indication for use
    • – Type of application: initial or amendment
    • – Who monitors the clinical trial(s)
    • – Clinical phase(s) of investigation covered by IND
    • – Defines trial responsibilities: Sponsor? CRO? Both?
    • – Commitment that Sponsor agrees to comply with applicable regulationsSee FDA

       Investigator’s Brochure (IB)
    – The IB is a compilation and summary of non clinical data and clinical data (ifavailable) on an investigational medication

    • – Main elements
    • • Description of drug substance and formulation
    • • Chemical structure (if known)
    • • Description of in vitro activities and mechanism of action
    • • Summary of pharmacological and toxicological effects of the drug in animals and humans (dependent on earlier clinical studies)
    • • Summary of pharmcokinetics and disposition in humans (if available)
    • • Information on the drug’s safety and effectiveness

    – The IB is required to be reviewed annually by the sponsor and updated as new non clinical and clinical information become available. By the time an investigational drug reaches Phase III studies, as many as 15 editions of the IB may have been generated.
  8. Contents of Commercial IND

         - Clinical Protocol
    - In the initial IND submission only the protocol for study to be initiated at the end of 30 day waiting period are included in the application. The IND is amended at later time with additional protocol.

    • – Main Elements
    • • Protocol title, ID number, sponsor & monitor’s name/address
    • • Investigators’ names/addresses for proposed study(ies)
    • • Background information on the investigational drug
    • • Objectives of trial
    • • Design of trial
    • • Selection (inclusion & exclusion criteria)
    • • Conditions for withdrawal of subjects
    • • Treatment of subjects
    • • Assessment of safety & efficacy
    • • Statistical methods
    • • Confirmation of direct access to source documents
    • • Ethical considerations
    • • Data management procedures

    Chemistry, Manufacturing, & Controls (CMC)
    – The objective of the CMC section is to establish that the methods used to manufacture and assay the investigational drug are adequate to ensure the safety of the drug.

    • Does the chemistry or manufacturing process pose potential human risk?

    Main Elements

    • • Information on Drug Substance: Active Pharmaceutical Ingredient (API)
    • – Chemical/Chemotherapeutic
    • – Peptides
    • – Proteins
    • – Biologicals
    • • Chemical description of investigational drug
    • • Who is the manufacturer?
    • • Method of manufacture
    • • Purity
    • • Define analytical limits & analytical methods to ensure identity from batch to batch
    • • Determine Stability (Expiration)
    • • Information on Drug Product: Formulation of investigational drug
    • • Example Formulations:
    • – Tablet
    • – Capsule, Caplet
    • – Injectable
    • – Inhalant
    • – Cream/Ointment
    • – Solution, suspension
    • – Suppository

    • Drug Product = Drug Substance + Excipients

    • – Notes
    • • Final formulation and manufacturing processes required by initiation ofPhase III Studies
    • • Purity of investigational drug depends on state of development
    • – For non clinical pharmacology, in vitro testing: 95%
    • – For non GLP toxicology, pre-formulation studies: 95%-98%
    • – For GLP non clinical toxicology & human studies: >98%
    • • All impurities >0.1% must be identified in the CMC section of the NDA
    • • No single impurity can exceed 1% in final manufacturing process detailed in NDA
  10. Excipients
    • Excipients: Pharmacologically inactive ingredients
    • – Why use excipients?
    • » Control release of drug substance
    • » Improve bioavailability
    • » Enhance drug dissolution
    • » Promote stability (e.g., protect from stomach acid), shelf life
    • » Aid in manufacturing (fillers, lubricants, wetting agents, solubilizers, adhesives)
    • » Mask unpleasant taste of drug substance
    • » Aid in identification of product

    • – Acceptable excipients, i.e., pharmacologically inactive & safe, are listedin the Orange Book and standards and testing details for excipients arelisted in the U.S. Pharmacopeia & National Formulary
    • – Example Drug (Prilosec) Excipients
    • » Cellulose
    • » Disodium phosphate
    • » Hydroxypropyl methylcellulose
    • » Lactose
    • » Mannitol
    • » Sodium lauryl sulfate

        - Non Clinical Pharmacology and Toxicology
    Main Elements

    • • Pharmacology & pharmcokinetics (ADME)
    • • Integrated GLP toxicology summary
    • – Objective: To provide FDA animal safety        data to determine if theinvestigational          drug is sufficiently safe for human studies
    • – Description of study designs
    • – Animal toxicokinetic findings
    • – Identification & qualifications of              toxicologists interpreting data
    • – Where studies were conducted
    • – Where studies archived for FDA inspection– GLP Certification: declaration that each study was conducted accordingto GLP standards
    • – Full toxicology tabulation (line listings) of individual data points and labdata for each animal

    Institutional Review Board

    A Local or Central (Regional) IRB must by law approve all clinical studies(i.e., drug and non drug) conducted in human subjects in the United States (and other ICH signatory countries) before the clinical trial begins (i.e., before the 1sthuman subject is enrolled).

    Local IRB: the IRB available to clinical investigators at large hospitals and university medical centers

    Central IRB: the IRB available to clinical investigators at small clinics/hospitals and investigators in private practice

    • – At the minimum, the IRB must review and approve before the study begins:
    • • Clinical Protocol
    • • Informed Consent Form
    • • Investigator’s Brochure
  13. Objectives of IRB review
    • – To ensure that risks to human subjects are minimal and reasonable in relation toanticipated benefits and disease for which the investigational drug is intended to treat
    • – Selection of subjects is equitable
    • – Informed Consent Form (ICF) is consistent with federal, local, and institutional regulations
    • – The ICF provides prospective subjects the requisite information for the subject to provide an “informed consent” to volunteer
    • – Study subjects’ confidentiality is protected
    • – That study safeguards exist to protect the rights and welfare of vulnerable subjects
  14. Other study-related responsibilities of the IRB
    • – Review & approval of study advertisements, including posters, radio & TV scripts, any documentation about the trial provided to the subjects
    • – Review/approval of Amendments to the study protocol & revised ICFs
    • – Review of IND Safety Reports (generated by the Sponsor)
    • – Review of Serious Adverse Event Reports (generated by the investigator)
    • – Review of annual study report (generated by investigator)
    • – Annual re-approval of study
  15. Required composition of the IRB
    • – At least five members with the appropriate expertise in some aspect of clinicalresearch or scientific background to review the clinical research programsbrought before the committee (physicians, nurses, phamacologists, pharmacists,etc.).
    • – One member must have a primary vocation in a non medical or non scientific area(e.g., social worker, member of the clergy, community activist, attorney)
    • – Must comprise mix of male and female members
  16. IRB Notes
    • – The IRB may halt a study at any time
    • – Conflicts of interest of committee members must to avoided
    • – A majority (> 50%) of votes is needed to approve a study, however each IRB may decide the percentage > 50% that constitutes approval
    • – Although the Federal Government has established “rules” (21 CFR 56) governing IRB activities, the government does not mandate IRB rulings. E.g., two IRBs reviewing the same study may reach different conclusions with one approving and one not approving the study.
    • – IRBs also must approve non investigational drug studies, e.g., studies relating todisease pathophysiology
    • – IRB committee members may be paid for their services
    • – IRBs usually charge for their review services, which are typically paid by the sponsoring pharmaceutical company

    Informed Consent Form
    • – Consenting prospective study subjects is a process whereby the subject does notenter a clinical study against her/her will or without adequate understanding ofthe study and its risks.
    • – Federal Regulations state:
    • • “. . . No investigator may involve a human being as a subject in research . . .unless the investigator has obtained a legally effective informed consent of the subject or the subject’s legally authorized representative. An investigator shall seek such consent only under circumstances that provide the prospective subject . . . the opportunity to consider whether or not to participate and that minimize the possibility of coercion or undue influence. The information that is given to the subject . . . shall be in language understand able to the subject.”
    • – The ICF is a legal document which describes the objectives, procedures, and risks associated with the trial. The participating subject (or legal representative) must understand the ICF and provide a signature indicating his/her under-standing and agreement to participate in the trial. The principal investigator or other clinical personnel involved in the study must also sign. Some IRBs will require a witness to sign.

    • – Principal Elements (dictated by 21 CFR)
    • • Statement that study involves research; objectives, duration, description of procedures; identification of experimental procedures
    • • Description of risks & discomforts
    • • Possible benefit to subject & others as a result of participation
    • • Disclosure of alternative sources of treatment
    • • Confidentiality procedures
    • • Reimbursement/Compensation
    • • Statement that participation is voluntary and that subject may withdrawal from study at any time for any reason
    • • Risks to fetus, if appropriate
    • • Circumstances under which a subject’s participation may be discontinued
    • • If placebo or comparat or arm, chance of being assigned to placebo or comparator group
    • • Plus state and/or local requirements

    Selecting Clinical Investigators
    • – A physician (MD, DO), but not always
    • – Experience in therapeutic field
    • – Qualified to handle medical emergencies or has qualified sub-investigator
    • – Experienced in clinical trials
    • – Access to target patient population– Not involved in competing clinical trials
    • – Has access to facilities specified in protocol
    • – Agrees to abide by clinical protocol
    • – Investigator has proper support staff (sub-I, Study Coordinator)
    • – Investigator has not been restricted nor debarred by FDA
    •     • FDA “for cause” audits & FDA Warning          Letter worrisome

    • – Note
    • • Sponsor or CRO will conduct pre-study      evaluation or qualification visit            toensure investigator can successfully  conduct study
  19. Form FDA 1572 (entitled Statement of Investigator)
    • – Essentially, Form 1572 is a legal contract between the principal investigator andthe FDA.
    • – The primary intention of the 1572 Form is to ensure that the principalinvestigator will perform the study according to the clinical protocol, and
    • • Personally supervise the study
    • • Use and ICF approved by an IRB; inform subjects that they may be assignedto a control group
    • • Report Adverse Events (AEs) to the Sponsor
    • • Read/understand the IB and potential risks of the trial
    • • Supervise other trial participants (sub-investigators, study coordinator, etc.)
    • • Keep adequate and accurate records
    • • Ensure that the IRB meets Federal requirements

    Investigator Financial Certification (FDA 3454) Disclosure (FDA 3455)Forms [Financial Interests and Arrangements of Clinical Investigators]
    – Objectives

    • 1. To make FDA aware of possible financial conflicts of interest of principal and sub- investigators participating in clinical studies
    • 2. Certification that no financial arrangements with an investigator have been made where study outcome could be affected by financial compensation

    – PI & sub-I must report financial interests with sponsoring pharmaceutical company for:

    • Stocks, honoraria, payments, copyright/licensing/patent/trademark agreements that result in payments that satisfy the types of financial payments below:

    • – Equity interest payments > $50,000
    • – Significant other payments ≥ $25,000 (not relating to direct payment for conduct of clinical trial)

    • Investigator Financial Disclosure Forms

    • – Actions if FDA may take to ensure the reliability of the data if it determines that the financial interests of any clinical investigator raise a serious question about the integrity of the data including:
    • • Initiate audits of the data derived from the clinical investigator in question
    • • Request that the sponsoring pharmaceutical company submit further analyses of data, e.g., to evaluate the effect of the clinical investigator's data on the overall study outcome
    • • Request that the sponsor conduct additional independent studies to confirm the results of the questioned study
    • • Refuse to treat the covered clinical study as providing data that can be thebasis for an agency action
    • Other Requirements (FDA- and/or Sponsor- Required)

    • – Protocol page signed/dated by principal investigator
    • – IRB committee roster or statement of compliance
    • – CVs & medical licenses of principal and sub- investigators
    • – Laboratory certifications & normal ranges
    • – Pre study evaluation report (unless waived by Sponsor)
    • – DEA 222/223 forms if controlled substance used
    • – Any necessary export/import licenses
    • – Executed contract between site/sponsor or site/CRO
    • – Letter of indemnification (if not part of investigator contract)
  22. Counterfeit Drugs
    • – Counterfeit drugs are a growing problem worldwide
    • – WHO (World Health Organization) estimates counterfeit drugs account for8% -10% of global medicines
    • – Estimates suggest that by 2010, counterfeit drugs will generate $75 billionin revenue!
    • – High profits & low risks for counterfeit manufacturers = deadly combination,especially as relating to drugs for serious or life-threatening conditions
    • – At present, most counterfeit medicines are manufactured in Asia and endup in the USA & Europe
    • – Major sources of counterfeit drugs are unregulated internet sites that sellmedicines
    • – FDA is developing guidelines in an attempt to make the drug supply chain more secure from counterfeiting
    • Parallel Study 
    • Cross-Sectional Design
    • Cross-Over Design
    Degree of “Blindness”

    Open Label Study

    • A non blinded study. All participating parties know the treatment groupwhich to which the study subjects have been assigned. In many open labelstudies, there is only one treatment group with all subjects receiving thesame treatment (e.g., the investigational drug at a single dose).

    Single Blinded Study

    • Investigator and possibly study staff know the treatment group to whichstudy subjects have been assigned

    Double Blinded Study

    • Neither the investigator nor other study personnel nor study subjects knowto which treatment group the subjects have been assigned. In fact, no oneknows to which treatment group the subjects are assigned except the individuals at the Sponsor or the CRO that generated the Randomization Code, which is kept under lock and key until Database Lock.

    • – Note
    • • The greater the degree of blinding in a clinical trial, the more expensive thetrial.

    • – The process by which subjects are randomly assigned to treatment groups
    • – Usually, randomization is performed by a computer program
    • – Ensures validity of tests for statistical significance of study data
    • – Attempts to provide approximately equal distribution of study subjects assigned to different treatment groups. In reality, rarely possible to have equal numbers of study subjects per treatment group.
    • – It is not a process to ensure equal distribution of characteristics between treatment groups (Stratification)


    • – A process to ensure either equal distribution (or distribution defined by the protocol) of certain characteristics among treatment groups
    • – Examples: male vs. female; weight range, intensity of pain, disease severity
    • – Usually done by “manual” inspection of randomized subject characteristics during the trial
    • – Stratification of subjects may be “controlled” during the study as necessary todecrease/increase enrollment of subjects with certain characteristics as required

    – Two different drugs, the same drug manufactured by different processes, or the same drug manufactured by different companies are bioequivalent if:

    • • Their absorption rates from the GI system exhibit a high degree of similarity,and
    • • their other ADME properties exhibit a high degree of similarity

    (Example: Generic drug may be marketed once patent on Brand drug expires. FDA will approve ANDA for Generic drug contingent on being chemically identical w/ Brand name drug and bioequivalent)

    Therapeutic Equivalence
    – Different drugs are therapeutically equivalent if they produce approximately equivalent effects in regard to a patient’s response (i.e., efficacy) regardless of dosage or the formulation of the drugs used.
    FDA sets the general standards for clinical research

    – FDA maintains and enforces GCP

    FDA protects the rights and as much as possible the safety of subjectsparticipating in clinical trials (but cannot guarantee safety)

    • – FDA ensures that clinical subjects:
    • • Are not exposed to unnecessary risks
    • • Are exposed to the least possible risk balanced against the anticipatedbenefits
    • • Give their informed consent prior to participating in a clinical trial

    FDA will advise the sponsoring pharmaceutical company to determine whatdata is needed to establish a drug’s safety and efficacy

    • – Meetings with the Sponsor
    • – Via published hundreds of “Clinical Guidelines/Points to Consider/RelatedGuidelines” for clinical evaluation of many classes of investigational new drugs
  29. GCP

    • Since FDA approves drugs based on data obtained from clinical studies, the agency has a vested interest in these data and the conditions under which the data were obtained. Thus, through a set of regulations and guidelines,collectively referred to as GCP, the FDA has established a set of minimum standards for the conduct of clinical trials.

    – GCP has two principal objectives

    • • To ensue the quality and integrity of the clinical data
    • • To protect the rights and welfare of clinical subjects

    • – Notes
    • • There is actually no single government document entitled “GCP.” Instead,GCP comprises federal regulations (21 CFR) and guidelines from a variety of FDA-published documents, many if which incorporate ICH recommendations.

    • GCP regulations and guidelines continue to evolve
    Responsibilities of the Sponsor or CRO

    Select qualified investigators as attested by the documents listed below

    • • Form FDA 1572
    • • Signed study protocol
    • • Investigator CV
    • • Financial disclosure

    Select qualified personnel to manage & monitor the study

    • • Qualified, adequately trained Clinical Research Associates (CRAs) to monitor sites
    • • Must have written monitoring SOPs
    • • Conduct pre-study evaluation visits of prospective sites (occasionally waived)
    • • Conduct periodic interim monitoring visits of clinical sites
    • • Review subject source documents and Case Report Forms (CRFs)
    • • Generate a written record of site monitoring visits
    • • Review of sites for compliance to GCP/ICH & protocol
    • • Sponsor or CRO site audits
    • • Medical monitor (Sponsor or CRO physician) on call

    Inform & train investigators and their staff

    • • Investigator meeting, IB, regular newsletters, publications
    • • IND Safety Reports generate by the Sponsor

    Adequate study-related record keeping & retention

    • • Source documents & CRFs
    • • Drug shipment to site & receipt
    • • Ensuring proper disposition of used and unused investigational study medications
    Responsibilities of Investigators

    Control of investigational drug(s)

    • Record keeping and retention
    • • Drug accountability records
    • • Subject-related study data & pertinent observations (Source Documents)
    • • Transfer of relevant Source Document data to Case Report Forms
    • • Study records must be retained for 2 years after market approval or discontinuation of the IND
    • • FDA, the Sponsor/CRO must be allowed access to these records

    • Generation of study-related investigator reports (for Sponsor/CRO)
    • • Case Report Forms (CRFs) (paper or electronic)
    • • Lab reports
    • • Special test reports
    • • Serious Adverse Event (SAE) reports

    • Assurance IRB review
    • • Site & personnel complying with all regulatory requirements
    • • Any changes of research activity reported to IRB• Protocol violations/deviations reported to IRB
    • • New unanticipated risks to study subjects reported to IRB
    • • Sent IND Safety Reports from investigator
    • • Ensures review/approval of protocol amendments before implementing
    • • Ensures review/approval of ICF due to amended protocol
    • • Ensures review/approval of procedural changes for subject recruitment
    Responsibilities of the IRB

    • – Ensures that risks to study subjects are minimized & reasonable in relation to the anticipated benefit
    • – Subject selection is equitable
    • – An ICF is obtained for each study subject screened
    • – The ICF must accurately represent the study and its associated risks
    • – Review/approval of study protocol (and protocol amendments, as appropriate)
    • – Adequate provisions exist for subject safety
    • – Subject confidentiality is protected according to current legal standards

    • The traditional pathway to approval, Phase I to Phase III, may be markedly different when a new drug offers significant improvement in therapy for serious or life-threatening illnesses or the new drug represents a “first therapy.”

    Phase I Clinical Studies
    Primary Objective: Determination of safety & tolerability of investigational drug

    • • Determination of ADME characteristics
    • • Drug – drug interactions
    • • Assessment of pharmacodynamics (vitals & lab evaluations)

    Trial Structure

    • Healthy, young volunteers, usually male

    – Exception: rDNA-derived drug, drugs w/ some toxicity, & drugs targeting serious or life-threatening diseases may use patients with target disease

    • • Limited number of subjects: ~10 initially, 20-30 in later studies
    • • Cross-over design w/ washout common
    • • Low dosages initially (based on animal safety); escalation to higher dosages until plasma levels reach pharmacologic concentrations
    • • Usually open-label
    • • Where conducted: typically in Phase I/GCRC unit in private or public hospital (to support ADME assessments)
    • • Subject assessments
    • – Vitals, blood chemistry, hematology, urinalysis, renal & liver function tests
    • – Blood draws, urine collection to provide data for ADME
    • • Studies of short duration: 1-2 weeks

    • – Notes
    • • Phase I will comprise multiple distinct studies; initial studies assess tolerability, while later studies assess tolerability and ADME characteristics (Toxicokinetics)
    • • If subjects with target disease used, an initial assessment of efficacy may be obtained

    • Phase II Clinical Studies
    Primary Objective: Therapeutic Exploration

    • To identify experimental conditions for conducting Phase III Studies

    • – Evaluate feasibility of clinical endpoints
    • – Identify patient population most likely to show efficacy for Phase III Studies (mild, moderate, or severe disease)

    • To identify minimal dose that produces the desired level of efficacy

    Trial Structure

    • • Use of test drug in patient population with target disease (probably for the first time)
    • • Assessment of effect of age, sex, concomitant illnesses, ethnic differences on ability of test drug to exhibit efficacy
    • • Identification of drug-associated adverse events (Safety)
    • • 50-200 subjects per trial, multi-center, diverse geographically
    • • 1 – 3 treatment arms plus placebo or comparator common design
    • • Subjects randomly assigned to treatment arms
    • • Double-blinded design common

    • Identification of key clinical endpoints

    • – Primary endpoint
    • – the more objective/quantitative the better; e.g.,decrease in viral load, tumor reduction, change in CNS lesions, lesion size
    • – Secondary endpoints
    • – may be less objective; e.g., cognitive measurements, QoL
    • – Surrogate endpoints
    • – a clinical endpoint related indirectly to effect of the investigational drug; e.g., CD4+ in HIV
    • – More ADME and pharmacodynamic determinations
    • – More drug – drug interaction assessments

    • Notes

    • – The Phase II program of the three clinical programs often comprises the greatest number of clinical trials, which may be conducted sequentially, concomitantly, and overlapping (w/ latter most common)
    • – The Sponsor may file an NDA at the end of the Phase II Program with highly statistically data when the test drug represents a major advancement in the treatment of a serious/life-threatening disease.
    • – At the end of the Phase II Program, the Sponsor will typically meet with FDA (“End of Phase II Meeting”) to ensure the safety of the test drug before proceeding to Phase III. FDA will also critique the Phase IIstudies and provide recommendations on the structure of the Phase IIIstudies. The goal is for the Sponsor and the FDA to reach agreement onthe design and adequacy of the proposed Phase III studies. If FDA believesthat the Sponsor is not ready to initiate Phase III studies, theFDA may recommend more Phase II studies!

    Phase III Clinical Studies (“Pivotal” or Registration Studies)
    Primary Objective:

    • • Confirmation of drug safety and efficacy with a prescribed regimen
    • • Confirmation of therapeutic benefit
    • • Provide data to support marketing approval
    • • Establish drug labeling

    Trial Structure

    • • Similar to Phase II but more study subjects
    • • Several hundred to several thousand with disease
    • • Further exploration in regard to age, sex, ethnic groups possible
    • • Study population must be sufficiently homogeneous so that variability to drug response is minimized, but the population must be adequately representative to ensure that the results apply to the general population
    • • Multi-center, expanded geographical testing (N.A., S.A., EU, Japan, Australia,perhaps, Thailand, Central America, South Africa)
    • • Typically double-blinded, placebo- or comparator- (“standard of care”)controlled

    – Notes

    • Since the outcome of the Phase III studies are the most important to the FDA in determining whether to approve the NDA, Phase III studies must be conducted with high scientific standards:

    • – Must be adequately controlled
    • – Usually must have blinded design
    • – Study subjects must be randomized
    • – The pivotal study must be of adequate size to provide statistical significance (p < 0.05) when comparing treatment group against control group

    • FDA will usually require two Phase III studies

    • Following completion of Phase III studies, and during the NDA review period, FDA will audit selected clinical sites to ensure the integrity of the data submitted in the NDA.
  36. DSMB & IDMCs
    • Data Safety Monitoring Boards (DSMBs), Independent Data Monitoring Committees (IDMCs)

    – A DSMB comprises qualified clinicians, scientists, statisticians, etc.independent of the Sponsor organization to assess safety and/or efficacy of an investigational drug at intervals during the clinical trial.

    – The DSMB must have access to the unblinded data and may recommend as a result of their analysis to stop a clinical trial for safety or efficacy reasons.

    – The DSMB may also recommend that the clinical trial be continued. In the event of continuation, neither unblinded data nor results are provided to the Sponsor.
    Clinical Site Personnel

    • – Principal Investigator (PI), Sub-investigator(s)
    • – Study Coordinator or Research Coordinator
    • – Study Nurse
    • – Pharmacist, Pharmacy Technician
    • – Special Medical Personnel
    • • X-ray or MRI Technician
    • • Radiologist
    • • Phelbotomist
    • • Lab Technicians

    • Study Subjects

    • Personnel Representing the Sponsor or Contract Research Organization(CRO)

    • Clinical Research Associate (CRA)
    • – Research Associate (RA)
    • – Project Manager (PM)
    • – Clinical Trial Manager (CTM)
    • – Medical Monitor/Safety Officer
    • – Clinical Data Manager
    • – Biostatistician
    •        • Randomization Coding Group
    • – Financial Analyst
    • – Medical Writer
    • – Clinical Quality Assurance
    • – Regulatory Affairs
    • – Manufacturing
    • – Drug Labeling & Shipping
  38. Source Documents
    • - Special Test
    • - Lab Results
    • - Progress Notes, Vitals,PE, AEs, Conmeds, Drug Acct, Compliance
  39. CRF
    The Case Report Form CRF contains the protocol-specified data resulting from the trial.Typically, the CRF is organized using the visit-by-visit format. The datadocumented in the CRF is the principal source of data used to construct thedatabase. Study-specific data also derives from lab tests and other specialtests.

    • Notes

    – How the CRF is designed is critical to the success of the trial.

    – The CRF and results from labs and special tests must capture ALL the data needed to make decisions regarding the safety and efficacy of the investigational drug

    – The CRF must be straightforward for the clinical staff, especially the study coordinator, the CRA monitoring the CRF against the source documents, and Data Management personnel.

    – The CRF may be hard copy (3 part NCR paper) or electronic (e CRF or EDC).– A CRF may range from 50 to several hundred pages depending on the complexity and duration of the protocol.
  40. Per 21 CFR 312.32, an AE occurring in a subject participating in a clinical trialthat results in any of the outcomes below is defined as a Serious Adverse Event(SAE)
    • • Death
    • • Life-threatening experience
    • • Persistent or significant disability/incapacity
    • • Congenital anomaly/birth defect
    • • In-patient hospitalization or prolongation of existing hospitalization
    • • Significant medical event requiring medical or surgical intervention to prevent any of the above outcomes
  41. Form FDA 3500A
    Med Watch Form - The sponsor or CRO will use one of several formatsfor the IND Safety Report with the Med Watch Form being the most common.