Module 1

center for drug evaluation and research (CDER)

"The mission of FDA's CDER is to assure that safe and effective drugs are available to American people" Various drug review divisions (based on therapeutic area) so expertise within each area is more focused. Review Divisions process and evaluate investigational new drug applications (INDs) and new drug applications (NDAs). Identifies whether a study should start, and whether they meet criteria for safety/efficacy. Must be consistent and have an understanding of what FDA expects to accomplish. Function under same legal and regulatory framework, i.e., have standardized policies and procedures. Each led by a division director (usually a physician), contains individuals from various disciplines (medical, non-clinical pharm/toxicology, chem, biopharaceuticals, microbiology for anti-infectives and sterile-products Benefits of generic drugs - less costly! spending less research on a drug that shows similar bio availability to the original product = lower cost. More of an evaluation of the biological or chemical property to see if those data points can be transferred to determine safety and efficacy of our generic drugs.

What makes a site standout?

(in the eyes of a sponsor) -rapid start up -intense screening -enrollment! -interested, responsive PI (tells us you're interested from a passion) -low "lost to follow-up" rates -clean data (less queries) -customer service (not only to the sponsor, but to the patients) -low screen failure rate (less work if you have less patients dropping out) -show a real differentiation between active treatment vs. placebo (double blind study)

How to find subjects

(site manager talking to recruiter) -advertisements (newspaper, radio, internet, clinicaltrials.gov, site's website, newsletters) -MD/NP/RN/resident referrals -admission reports (any patients in our facility good candidates?) -lab reports -procedural results

A day in the life of a site

**following IRB approval -screening -recruitment (need advertising?) -enrollment -protocol follow-up -closure of study (planning for that at the beginning) -PAPERWORK

Different Country's Regulatory Bodies or Regulatory Agencies

-European Medicine's Agency (EMA) -PMDA Pharmaceuticals and Medical Devices Agency -Health Products and Food Branch of Health Canada -National Health Surveillance Agency (NHSA) -Drugs Controller General of India (DCGI) -China Food and Drug Administration (CFDA) FDA consistent thread of standardization through use of GCPs and ICH principle Each RA has its own rules -make sure you're familiar with requirements prior to study ** a few times when regulatory approval not required: -post-market studies -low risk medical devices

IND Contents

-FDA Form 1572 (identifies investigator who will be accountable for initial trial) - investigator and contact info provided, signs off accountability and oversight of patients -table of contents -introductory statement and general investigational plan -investigator's brochure -clinical protocol -chemistry manufacturing and control information -pharmacology and toxicology info -previous human experience -additional info (i.e. abuse potential, pediatrics studies...) -misc. relevant information

Emergency Use IND

-IND for "compassionate use" or "single use" -first step: physician needs to obtain permission from manufacturer -if manufacturer agress, the document management branch is called or the FDA Division of emergency of epidemiology during non-office hours -Approval conditioned on sponsor submitted appropriate IND documents ASAP after authorization

Regulatory Documents

-PIs and subinvestigators CVs -Lab "normals" and certifications -IRB membership (if local) -FDA Form 1572 (done by PI) -Financial disclosure -Protocol signature page -Addresses for contracts and drug/supply shipments BEFORE A DRUG CAN BE DELIVERED TO SITE: -IRB approval of protocol and consent (all documents in the site study file, and sponsor's master file) -membership list of all IRB/Ethics Committee members at each site -signed protocol page (including signature of the sponsor rep and site rep) -financial disclosure form -1572 (identifies the accountability of the PI and key site staff for quality and safe conduct) -disclosures of significant risk (the person may still be able to be involved, but needs to be disclosure) -all current CVs -certification of this lab and the normal ranges

Informed consent process

-VERBAL if possible, at least a synopsis (phone or in-person) so we can tell if participants understand -participant MUST read written document or have it read to them (why we make sure it's available on tape) -reiterate most important issues: risks, obligations, benefits, procedures -LAY LANGUAGE! (about 5th grade level) -participants receive a copy of ICF 1. The consent discussion: -give as much time as possible for decision -include as many support persons as possible - spouses, children, physicians -if possible, leave ICF and return after time to read and discuss -have script to use for discussion - make patient comfortable and be careful not to coerce 2. A process... -consents may change - updated for procedural changes, length of time of study, number of participants -adverse events that participant must be aware of to continue participation (what are the risks? how will we keep you updated of changes?) -ongoing awareness that they may discontinue at anytime for any reason! -HIPAA special issues 3. Informed Consent: Standard elements required: -purpose of the study -statement that study involves research (no guarantees - must be known) -expected duration of subject's participation -description of procedures -why subject is a candidate for participation -# of subjects locally and nationally -potential risks -potential benefits (equally governed by FDA - no overstate) -alternative treatments -confidentiality of records including publication of data -"voluntariness" - refusal to participate will involve no penalty or loss of benefits, can discontinue at any time -PI can terminate participation at any time without regard to subject's consent -consequences of subject's decision to withdraw -costs that might be incurred (who will pay research costs?) -Injuries -Payments -Significant new findings developed during course of study which may relate to subject's ongoing participation... -signatures -witness (a person who identifies that they have seen the person sign consent... they are not saying that person has been consented to full info... they are only witnessing the identity of the person!) 4. Attrition = DROP OUTS -may go from active stage to "observational mode"... may not feel like its bringing them value -site needs to evaluate what is the chance for dropouts?? make a plan -why do patients drop out? don't feel involved, don't feel that it's bringing value -when? perhaps when there's a change in activity with the patient, when something happens in the patient's personal life -how? sometimes patient doesn't show up! tries to contact... phone disconnected... for regulatory authorities that site has oversight of participants, they will need to see documentation of what site did to follow up -how to avoid? strong relationship building is key! takes a lot of time and resource. leads patient to feel they have a commitment and feel valued -coercion versus encouragement!

Site management: finances

-accountants may be involved in larger institutions -coordinators/managers need to know what type of financial interactions they will have -contracts and budgets (site vs. sponsor negotiations) -screening time -overhead that might be associated (lights, cost of machines...) -consultant fees (i.e. physician reading EKG or XR) -AE analysis and follow-up costs -patient budgets (how will site identify what cost would be for screen failures) -may be a grant department -keeping track of work done (accounting for finances!!) -keep track of money received -reconciliation - ongoing AND end of study **do not over estimate or under estimate budgets BUDGETS: Ex: coordinator breaks down all the resources/individuals involved, identifies areas within the protocol in which these people would be involved, then estimate how much time it would take for an individual to carry out their activities, add it up and look at avg cost per hour... have an idea of a budget

Sources of site selection

-could be monitors who have worked with sites previously or done cold calls -clinical teams may provide a source of site selection (maybe due to experience) -publications of key opinion leaders (KOL) -people they have met a professional meetings -investigators who the sponsor has worked with, referring associated professionals -contract research organizations (CROs) who may have worked with particular sites

Obstacles to a site's success

-delays in startup -PI loses interest or nerve (hopefully has a successor set up) -participants -busy/trial heavy physicians -protocol details (set up extra training) -staffing -finances Where is the challenge? -inclusion/exclusion criteria that is unclear -sponsors who are not readily accessible to discuss clinical issues -changing clinical practices -borderline eligible patients -patient excuses (too many visits, too far away, too many pills, too much blood to draw, no car, other responsibilities... even though they knew details from consent) "I don't want to be a guinea pig!" Never forget the IRB! -saw them at the start -require reports back to them at least yearly -continuing a study (CR) -changes to a study (amendments) -safety reports (should be sent on an ongoing basis) -when study is closed, put forward big summary to IRB -"when in doubt, report it out!" Never forget the IRS! (people who forget our taxes)

Treatment IND

-drug is under investigation in a controlled-clinical trial -Requested by a licensed practitioner if the sponsor will not establish a treatment protocol -viewed as a promising new drug for serious or life threatening disease for which no comparable drug therapy is available

Reasons for IND termination

-if subjects are exposed to unreasonable/significant risk -not enough sufficient info to assess safety -manufacturing principles are not sufficient to ensure that identity/strength/purity of product are solid, reliable, and valid -if they re-look at strategy, and identify that they are going to conduct trials DIFFERENT than stated in protocol -untrue or omitted facts that are key or critical -drug promoted or distributed for commercial purposes -if sponsor fails to investigate and report to FDA serious AEs (lack of oversight on part of the sponsor and investigators) -does not submit accurate report -clinical hold put on study and sponsor does not honor the hold -during conduct of the study, if it is shown to not be effective -investigational plan or protocol changed significantly enough

Regulatory Approvals: Clinical Trials

-need Investigational New Drug (IND) submitted to FDA -30 days to comments -if no comment, continue with study -CLass II and III devices need Investigational Device Excemption (IDE) -US has too many requirments to list MARKETING: -New Drug Application (NDA): US Non-biologic drug -Biologic License Application: (BLA) US biologics (including biosimilars) -Premarket Notification (510(k)): US Class 1 (rarely) US Class II (often) -Premarket Approval (PMA): US Class 1 (virtually never), class II (rarely), class III (virtually always) -Marketing Authorization Application (MAA): E.U. Drug or Biologic -CE Mark: E.U. Device

References

-protection of human subjects -financial disclosure by clinical investigators -institutional review boards -investigator's brochure -investigator record keeping and retention -FDA websites (www.fda.gov) -ICH Homepage (www.ich.org) 21 CFR Part__ or ICH #.#.#

Site Staff

-site manager: manages study coordinators at the site, coordinates other functional teams that are part of the clinical trial -principal investigator: experienced physician -recruiter: someone who is part of a call center, so when people respond to adds, screens potential study participants for inclusion/exclusion -pharmacist: manages potentially complex drug interactions - may need to reconstitute medication. Delivers medication to patients, and responsible for inventory of investigational product Sub-investigators: additional physicians to help PI, skilled in their medical practice -study coordinators: led by site manager, make machine work, strategize operations, bring patients in, first line responders for patient communications, work to keep patients in the study -regulatory document specialist: supports coordinating by gathering and completing documents, coordinates with legal and grants specialists to ensure that contracts and budget are approved -ethics committee: Objective group who will give approval to begin study. offers recommendations to the protocol, or indicates that the study is good. works to protect the rights of patients -scientific review consultants: provide input regarding scientific merit of study. may be a peer group of PI that is asked for recommendations. sponsor also uses consultants for input. -grant administrator: responsible for study's overall budget. provide financial guidance and recommendations -legal consultants: provide legal guidance and protection on contractual issues such as HIPAA, conflict of interest, and coercion -corporate communication: advertise the study to help bring patients in. communicate the study's success to raise site profile POWERHOUSE: study coordinators. need to be clinically sound. good nurses/clinical staff, great assessment skills, excel in documentation, precise and follow the protocol by the book, know how many clinical trials to have

Sub Studies and Ancillary Studies

-usually sponsor-driven -occasionally site-proposed (asked if they can use some data or laboratory specimen to analyze some different area) -in healthcare today, push to control costs... if new product being proposed, what is the advantage from economic standpoint? may benefit healthcare long term and quality of life -could be genetic ancillary study -some studies include new procedures -can be two goals met by one intervention

Types of INDs

1. Initial IND (provided by a sponsor or investigator) - first time regulatory body has seen an IND of this type for this product -Sometimes investigators has more interest than sponsor... when an investigator may file the IND (sometimes sponsor support this) -Person who submits the IND first is considered the person who holds the IND 2. Treatment IND 3. Emergency use IND (dire need of a drug/device, no other alternative treatment and immediate use must occur) 4. For future use, must go through approval process 5. Exploratory IND (a product is not yet determined where the best fit is)

Participants Responsibilites

1. SPONSOR - select qualified investigators, provide investigators with all the info needed to conduct an investigation properly, monitor the investigations, ensure the investigations are conducted in accordance with guidance of investigational plan and protocol, maintain up to date IND, ensure FDA and all participating investigators are informed of AEs or risks of the drug, record-keeping, ensure disposition of unused drug supplies and ongoing drug supplies 2. INVESTIGATOR - conduct study according to protocol and all accountability that they signed off on in form 1572 and other laws/regulations, obtain IRB approval prior to any dosing by the patient or any procedure being done, obtain informed consent, report any adverse experiences to the IRB or sponsor, keep accurate and current reports on study progress (updated case report forms), keep accurate study drug accountability (minimize any chance that patient will be dosed inaccurately), inform the study sponsor of any financial interest in the sponsor company, product, or study outcome

FDA Groups

1. center for drug evaluation and research (works closely with participants for clinical research) 2. center for devices and radiological health 3. national center for toxicology research (determine risks of products/drugs) 4. center for biologics (up and coming - differentiates pharmaceuticals from biologics) 5. center for veterinary medicine 6. center for food safety and applied nutrition (looks at foods, infant formulas...)

Summary of Drug Development and Review Steps

1. pre-clinical (animal) testing 2. an IND submitted that outlines what sponsor wants and purposes for human testing in clinical trials 3. phase 1 studies (20-80 volunteers) 4. phase 2 studies (few dozen to 300 patients) 5. phase 3 (several hundred to 3,000) 6. the pre-NDA period, just before an NDA is submitted **Common time for FDA and drug sponsors to meet if yes - document of NDA is submitted 7. NDA received, FDA has 60 days to decide whether or not to file it for review 8. FDA review team assigned led by project manager that will evaluate if there is enough info to support safety/efficacy of product 9. FDA will review info that goes into label and guidance on how to use the drug 10. inspect facilities where drug will be manufactured 11. drug application will be approved (or not) - if not approved, sponsor will receive complete response letter and be able to talk with regulatory body to discuss next steps

Key elements of informed consent

1. risk to fetus (required for pt population of child bearing age) - most require women be on birth control (sometimes 2 forms) ex: thalidomide 2. termination of participation (either 1. sponsor may terminate an individual's participation bc lack of compliance or safety/business reasons or 2. subject can stop if they change their mind) 3. any costs that patient will have to pay (sometimes not covered by insurance... sponsor will do everything they can to reimburse) 4. Consequences of early termination (may have to come back for one more visit to check for outstanding safety issues for their protection) 5. any new findings that occur during study will be provided to the PI who will share with the participants if needed 6. # of people involved in study 7. What are the unforeseeable risks? a sponsor doesn't know everything that could happen... that's why there's continuing research. but what they know from prior research should be shared. And identify that there could be other risks we don't know about. 8. Potential benefits (usually minimal piece.. ex: we do not know any potential actual benefit, but it could be your participation that may help future patients to benefit if study is a success) 9. Definitions of medical terms 10. opportunity for the patient to ask questions to the study staff after reading it

Criteria for IRB approval

1. risks to subjects are minimized 2. good benefit to risk ration 3. equitable selection of subjects 4. informed consent will be sought (in writing) 5. monitoring is planned by sponsor 6. subject privacy will be observed 7. subject rights will be protected

GLP Test and Control Article Characterization

1987 GLP revision allows companies to screen out many useless compounds before investing resource to characterize them Current regs allow facilities to conduct stability testing either bofore study initiation or through periodic analysis of each batch if possible

GLP Inspections

2 types: Surveillance (routine) Directed or "for cause" may inform regulatory agency if serious issues found common GLP violoations are with regard to equipment and SOPs (commonality with GCP) Informed consent and protocol compliance are the biggest two sources of violations for GCPs

Privacy Laws

5 main categories: -Health insurance portability and accountability act of 1996 (HIPAA): covered entities are required to protect patients' protected health information (PHI), requires study subjects to consent to disclosure of PHI. Sponsors/CRO not considered covered entities so HIPAA doesn't apply! -Health insurance technology for economic and clinical health (HITECH) Act: Permits compound authorizations, establishes a few restrictions on future research using previously collected PHI -State Privacy Laws: primary focus on consumer protections and are not relevant to clinical R&D, common sense/respect typically ensures compliance with state privacy laws -E.U. Data protection Directive (Directive 95/46/EC): applies to all personal info, much more comprehensive than HIPAA, establishes responsibilities of data controllers and data processors -Other Ex-U.S. Privacy Laws: varies by nation, so work with Privacy Officer or legal counsel

Biosimilar

A biological product: -highly similar to the reference product despite minor differences in clinically inactive components -must not differ in a clinically meaningful way from the reference product in terms of safety, purity, and potency Similar to a generic drug vs. brand drug, but generic drugs: -must be bio equivalent to the branded drug -typically don't require clinical trials to prove bio equivalence

Investgational Drug/Device

A drug/device in any of the clinical stages of evaluation (Phase I, II, and III, IIIB) which has not been released b the FDA for general use or cleared for sale in interstate commerce. - any commercially available drug/device proposed for a new use - a new drug dosage form or method of administration - a commercially available drug which contains a new component such as an exci

Predicate Device

A marketed device against which a new medical device must show substantial equivalence in order to receive marketing approval

A Doctor's Drug Study Turns into Fraud Article

A physician had a large clinical research practice and created data fraudulently. he was collecting info from his own staff and himself, then using that data to fabricate a patient. That was fraud - physicain lost his medical license and will never conduct a trial again. BLACK LIST - regulatory agencies hold and are public knowledge (CIs, IRB, or ECs who are not following regulations and ensuring quality)... sponsors make sure no one in their study is on this list

Key pieces of IRB Study

APPLICATION -IRB initial application (purpose of the study, duration, expected enrollment, study records security and destruction, HIPAA and informed consent issues, description of intervention including drug doses and times, anticipated risks and benefits, previous experience with efficacy and safety issues SUBMISSION -IRB initial submission (full, approved protocol, application or summary for lay members of committee, consent form - template from sponsor with site-required modifications, investigational drug brochure or IFU, other info: ads, informational materials, reimbursement for patients, safety reports, past research, questionnaires, device samples REVIEW -IRB has all written materials -IRB likes staff to come to present the study (tough group) -present protocol (PI) give overall synopsis of study -defend study against questions from committee (as simple as a forgotten "the" to unexplained AE) -emphasis on improving readability and understanding of ICF (define all words, explain all procedures, be clear and fair in risks and benefits, discuss alternatives) -wait for letter of approval! (receive an envelope in the mail) CENTRAL IRB -an IRB that covers all sites within a study or a program; external to the Agency -sponsors LOVE them: one stop shopping (one bill paid), one-stop pricing, one-stop approval, partner in getting the study up and running and keep it going -sites don't always want central IRB (want to feel more in control, so they use their specific IRB)... no local input/oversight

ADE

Adverse Drug Event/Experience

ADR

Adverse Drug Reaction

AE

Adverse Event A new or worsening medical occurance in a patient or clinical subject - does not necessarily have a causal relationship with the investigative treatment/product. (that determination is left to the PI - but, as regulatory authorities review the data, they may have a different opinion... that's why all AE are reported, no matter the relationship to the investigational product) Any unfavorable and unintended sign (abnormal lab, symptom, disease) temprarily associated with the use of investigational treatment and/or product.

FDAAA 2007

Amendment Act called FDAAA example of FDA changing in response to a very dynamic environment Many new provisions of the law, especially in the area of drug safety Expansion of NIH clinical trial registry to include all clinical trials, involving drugs, biologics, and devices except phase 1 studies that were normal volunteers (encouraged to list) Creation of a clinical trials results data bank to ensure more transparency of research out there and results of research

Blinded by Science Article

An individual at the University of Pennsylvania where IC was not comprehensive enough. There was a death of an adult because they agreed to participate not knowing all the risks because the risks were not captured in the IC IRB received sanctions following this and needed to tighten their process. Unit where research was being conducted also needed to re-evaluate and update their process

Subject Trial Subject Research Subject

An individual who participates in a research study, either as a recipient of the investigational product(s) or as a control. Also refers to any individual in any research study.

Sponsor

An individual, company, institution, or organization that takes responsibility for the initiation, management, and/or financing of a research study. ex: pharma company, biotech, medical device company, NIH... Responsibilities: -provide IRB and Ethics Committee with info/updates and answer any questions directed to them -provide the product -coding and labeling of a blinded product (in a double blind study) -record access to regulatory agencies (maintain a trial master file that can be accessed if being reviewed or audited) -providing study reports and sharing results on a website called clinicaltrials.gov (transparent way for sponsors to share positive value of products and when products are not positively outcomed) -overall accountability for quality of the study (why they employ monitors/contractors) -provide medical expertise (or may delegate to contract research organization) -create the trial and handle the data/archiving/result presentation -acocuntable for investigator selection -looking for ways to be more efficient (in collecting data and financing)

Research Study

An organized, detailed study/investigation/experiment of a fact, event, development or question of scientific interest susceptible to scientific description and explanation for the acquisition of new information and or a better understanding of existing information.

Life-threatening adverse drug experience

Any adverse drug experience that places the patient, in the view of the investigator, at immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction that, had it occurred in a more severe form, might have caused death. Objective/observable, and with the expertise of investigator, and determination of himself/herself, patient is placed at immediate risk of death. Not one person (not even the sponsor who developed it) knows all of the possible situations that these products may provide to potential patients. More information is received from each phase. The sponsor and future study sites will have a better idea of safety profile/efficacy as you move from phase 1 to phase 3. At times, there may be a situation that may not have occurred before, and be life-threatening.

Clinical Trial/Study

Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of an investigational product(s) and/or to identify any adverse reactions to an investigational product(s) and/or to study absorption, distribution, metabolism, and excretion of an investigational product(s) with the object of ascertaining its safety/efficacy any investigation in human subjects intended to discover or verify the clinical effects of an investigational device and/or to identify any adverse reactions to an investigational product with the object of ascertaining its safety/efficacy

Drug

Articles (other than food) intended for use in diagnosis, cure, mitigation, treatment, or prevention of disease OR intended to affect the structure or any function of the body

Food

Articles used for food or drink OR chewing gum

Site management: clean up, results, final thoughts

CLEAN UP: before data lock occurs, there needs to be assurance that all patients have been brought in, drugs returned, reconciliation, case report form filled out, queries answered. -achieve "data lock" when all that occurs aka data is frozen. -Could be some edits! -keep records close at hand... might need to provide answers last minute -new data requests (IRB questions) -rapid turnaround -what is reasonable? discussion with the sponsor how this will occur RESULTS: -data cleaned and results have come forward -late breaking clinical trial results possibly... more studies might be starting up -lots of publications (both from sponsor and maybe site members) -what was negotiated and what was the process for sharing results with participants? -how to "break the blind"? FINAL THOUGHTS: -did results show favorable benefit for the product? move forward in the development! -a better appreciation of each side (site v sponsor) may lead to more cooperation and improved relations -met a common goal - develop better EBP for patients -not just a view from the other side of the window... TRUE PARTNERSHIP between site and sponsor

CRF eCRF

Case Report Form electronic Case Report Form Printed, optical, or electronic document designed to record all of the protocol-required information to be reported to the sponsor on each trial subject. the document that data is entered into and uploaded for analysis of results (by a data analyst) to see if anything needs clarification

CDER division technical discipline: Chemistry

Chemistry organization reports to the office of new drug chemistry Review chemistry, manufacturing, and controls sections of drug applications. DEA = drug enforcement agency also involved with controlled substances. Act as consultants to identify if products are considered controls. Address issues related to drug identity, manufacturing, and control analysis.

CRA

Clinical Research Associate a key person who conducts monitoring at the site

CTA CSA

Clinical Trial Agreement Clinical Study Agreement The contract a sponsor has with the site to conduct the research

Supplemental NDAs

Clinical trials rarely end with the submission of the NDA! Supplemental NDAs are submitted for various reasons that will require additional clinical data to support product safety and efficacy due to changes such as: -changes in dosage strength or route of administration -change in formulation -new indication -new treatment population

CFR

Code of Federal Regulations Basis for FDA's recommendations for the conduct of clinical trials

Administrative/regulatory files

Collection of documents essential for a research study ex: IRB communications, ICF, protocols (may have multiple versions), protocl ammendments, 1572 (filled out by the PI - mandated for FDA IND studies), IDB, site visit records, site staff info, safety/general addenda, CVs of site staff, any professional licenses, lab normals/certification (more for local labs - central labs require one certification to be filed in the general file with the study), SAE's, drug supply correspondence (ie inventory records, reconciliation or accountability - many filed at the END of the study), sponsor correspondence, closure letter (what is submitted to IRB at the end), subject identification log (who the site looked at during the screening process, who was radomized, and also tying together the demographics of the subjects), miscellaneous, delegation of authority by PI (including when they were trained and their background qualifications), IVRS (electronically dispenses the coding/randomization code for the drug, and what package to pull for each patient), financial disclosures (done on an ongoing basis + one time after... all finanical conflicts of interest), study drug or device accountability records, equipment or supply records (include shipping labels, training records for staff) All kept in a binder that needs to be current and available for monitor to review Essential to start up a study, essential to keep them current during the study, and need to do a full reconciliation at the end of the study

international Conference of Harmonization

Consistent base agreement about how to conduct clinical trials... unique regulations for each country EU came together to be able to better consistently work across their borders. Not all countries fall under this union. Drug development regulatory requirement was one area they wanted to harmonize... more consistent way to work Incorporates EU, Japan, and United States in the guidelines. Both input in regulatory bodies and industries... so guidelines could be realistic and so there could be conversations about whats important to regulatory agencies GOAL - ICH guideline to reduce technical requirement between countries and agencies. This incorporates an approach that's safe and scientifically sound for the patient. Benefit from both sides. ICH and GCP objective: Provide unified standards for the EU, Japan, and United States to facilitate the mutual acceptance of clinical trial data by the regulatory authorities in these jurisdictions

CRO

Contract Research Organizations A person or an organization (commercial, academic, or other) contracted by the sponsor to perform one or more of a sponsor's trial-related duties and functions. many times, things are sent off-shore, they're outsourced... a CRO is a vendor that supplies these outsourced activities

CV

Curriculum Vitae resume

Informed consent DOs and DONTs

DO: - use accurate and understandable wording - inform subjects of those entities to which access to study records will be granted (i.e. regulatory/ethical bodies) - names and phone numbers of contact for: study subject's rights, research related injuries, study procedures - all study procedures in explanation - explanation concerning availability of medical treatment and/or compensation in event of injury - inform subjects of the circumstances under which their participation may be terminated without their consent - inform subjects that they may be withdrawn if they fail to follow investigator's instructions DON'T: - make a regulatory claim (can't promise something that hasn't been proven) - state or imply that regulatory body needs subject's permission to view patient records (2 BODIES THAT CAN REVIEW PT DATA W/O FURTHER PERMISSION - 1) regulatory agencies and 2) ethical bodies (IRB/EC)... of the protection of the participant... should be explained to them) - overstate... if no direct benefit to subject, that should be stated... or say there may be future benefit if product successful - merely provide a list of alternatives. explain all alternative therapy options, including their risks - minimize adverse effects - confuse compensation with medical treatment... not synonymous, must be addressed separately

DMC

Data Monitor Committee looking at the results obtained at a site and identifying whether these results show potential for safety and efficacy

Site management: finer details

Data collection method: (more detail later) -is this study conducted with paper or electronically? capabilities of study staff? -source documents (will there be a structured form? put into the chart? separate research chart?) -Standard Operating Procedures (SOPs) at sites for patient visits -analysis of "does the case report form make logical sense to the site staff?" otherwise more errors will occur -how to insert info into institution/practice's charts Protocol Procedures: -more precise protocol = better control in study (ex: take BP 3 times - 2 min apart after sitting for 10 minutes in a quiet room. collect all measurements and average the 3) -ex: 6 minute walk test and scripted conversations (a protocol should say to take the convo and script it! give site staff an opportunity to know how the sponsor is looking at this. more focused view) -site staff identify whether assistance by non-research staff is appropriate (if protocol is specific, consistency will occur)

Sample IRB Approval Letter

Dear ___, This letter is to notify you that your research protocol entitled _____ and the accompanying informed consent have been approved. We ask that you inform the IRB in writing of any serious AEs. Failure to do so will result in revocation of this approval. Changes to the study protocol must be submitted to the IRB for approval prior to the implementing, with the exception of emergencies, which may be subsequently reported. This approval is in effect for one year from the issuance of this approval. Sincerely, _______-

Biologic vs. Drug

Drug = small, simpler molecule -relatively simple to create in a chem lab -easier to analyze the final molecular structure Biologic = larger, more complex -derived from a living organism rather than chemically synthesized -so big and complex that its very difficult to analyze final structure

Waiver of Informed Consent in Emergency Situations

Emergency use means the use of a test article on a human subject in a life-threatening situation in which no standard acceptable treatment is available, and in which there is not sufficient time to obtain IRB approval. An individual on the verge of dying, and the site knows that they have a product that may help them.

Record keeping of IRB

Ensuring IRB promptly notify in writing the investigator/institution (sponsor) concerning: - trial related decisions/opinions - reasons for the IRBs decisions/opinions - procedures for appeal of its decisions/opinions

Drug and Device Legislation

FDCA (food, drug, and cosmetic act): describes requirements for securing marketing approval for drugs/devices at a high level -for drugs, the key requirement for marketing approval is to provide "substantial evidence" (drugs; not devices) of safety and efficacy -typically, 2+ phase III clinical studies showing that therapeutic benefit (i.e. increased survival) outweighs adverse event risk -consider adequacy of existing therapy, severity and frequency of adverse events, seriousness of disease Biologics Price Competition and Innovation Act of 2009 (BPCI) -establishes "biosimilar" pathway -biologic drugs mirror drugs (i.e. substantial evidence) -biosimilars typically require at least one clinical trial will be required to demonstrate that the biosimilar is highly similar to the marketed biologic Debarment Act: -pharmaceutical manufacturers must not use services or procure goods from debarred persons or entities -search FDA Debarment List (drug product applications) before working with anybody

FDA

Food and Drug Administration US regulatory body only (each country has their own) largest of all regulatory bodies we are going to approach things more globally Executive branch > department of health and human services > FDA approximately 10,000 staff members (some local, some in field offices around the world. headquarters in Maryland) Mission Statement: "The FDA is responsible for protecting the public health by assuring the safety, efficacy, and security of human and veterinary drugs, biological products, medical devices, our nation's food supply, cosmetics, and products that emit radiation" Ensures the safety of over 1 trillion dollars worth of products Organization -Divided up by therapeutic areas (when human products involved) -Divided into other areas that are non-drug product related (i.e. food, cosmetics, vet. products) -head of FDA = COMMISSIONER appointed by executive nomination and confirmed by congress (leads and strategizes about how regulatory body functions, assures adequate over site... ties into government - legislation and policy making going on, chief of staff = project manager, counselors) global colleagues - countries/sites filed under US IND follow our country's regulations as well as any further country regulation in their geographical region (we have auditors going to various countries and sometimes setting up an office) ex: India has become much more of a mega research area (costing, vast amount of pts, medical/scientific staff interest)

1572 Form

Front: 1. investigator name and address 2. training 3. location of investigation 4. where is lab 5. where is IRB 6. sub-investigators 7. name and number of protocols in IND that Back: -investigator is shown what their responsibilities are 8. protocol will be followed 9. safety 10. confidentiality of patients 11. signature of investigator

GCP/ICH

Good Clinical Practice International Conference of Harmonization logistical and operational aspects of what needs to occur when a clinical trial is occurring that will ensure quality and approval of results A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of a research study that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected. Come from the FDA regulations. Aims of GCP: 1. ensure rights and integrity of subjects are protected 2. establish data credibility 3. decrease risk of future patients of a product being used inappropriately 4. to improve the ethical/scientific/technical quality of trials Areas of coverage: 1. risk vs. benefit analysis 2. scientifically sound protocol 3. compliance with protocol 4. qualified study staff 5. informed consent 6. data accuracy (reporting and handling) 7. subject confidentiality 8. good manufacturing practice Key areas of assurance: - research data (credible, accurate, comprehensive) - research subjects (rights, integrity, confidentiality)

GLP

Good Laboratory Practices "GCPs of lab research" Formalized by FDA in 70s and apply to non-clinical regulations (so not including humans) Certain studies (very few) are exempt from GLPs. Very few because regulations seem to become for stringent and sponsors want to ensure they take their best portfolio forward Areas covered: - what is the standard of their facilities/equipment? -operational strategies and controls being conducted within study - same requirements of a protocol with records/reports needing to be maintained and submitted STUDY DIRECTOR (similar to PI): has full accountability that everything is held to highest quality. QUALITY ASSURANCE UNIT: neutral to study lab, provides an audit and ongoing review to ensure all controls are maintained with highest standards. follow thru with policies and procedures so study is seen as viable. data credible/comprehensive/controlled TESTING FACILITY MANAGEMENT: testing facility - needs to be managed (ex: temp requirements?). Must have STANDARD OPERATING PROCEDURES (SOPs) GENERAL PERSONNEL - general expertise and what they need to possess to ensure GLPs being maintained 12-item protocol - protocol is study specific -SOPs are standards used for all research projects at a given facility

GMP

Good Manufacturing Practices how product is created... introduced in early 60s (when impurities were found in products) quality is an ongoing review (not just tested at the end) - each step outlined under SOP's must be audited. Inspections usually conducted on an impromptu basis Looked at and audited by regulatory bodies, including FDA (ex: tylenol contaminated with cyanide) Areas: 1. organization and personnel 2. buildings and facilities 3. equipment 4. control of components and drug product containers and closures 5. production and process controls 6. packaging and labeling controls 7. holding and distribution 8. laboratory controls 9. records and reports 10. returned and salvaged drug products

HIMS

Health Information Managment Services how are health apsects handled on a patient? how is the information transferred? who is it transferred to?

HIPAA

Health Insurance Portability and Accountability Act our government's quest to ensure confidentiality of patient data

HHS

Health and Human Services

Monitoring

How the sponsor has oversight of everything... The act of overseeing the progress of a research study, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, standard operating procedures (SOPs), Good Clinical Practices (GCP), and the applicable regulatory requirements. Monitoring Visits are performed by a Sponsor or Contract Research Organization (CRO) representative, usually a Clinical Research Associate (CRA).

Regulatory agencies (FDA)

IRB/EC are accountable to RA and participants -audit trial sites and sponsors -obligation to review IRBs and ECs DUKE UNIVERSITY ARTICLE: IRB came under scrutiny by FDA - did the medical experiment that was approved by IRB provide needless risk to patients in the study?? outcome of investigation identified that Duke's IRB needed to tighten up policies, procedures, and documentation UNIVERSITY OF OKLAHOMA ARTICLE: regulatory agency/FDA stopped a study for safety issues - sponsor is a business funding a trial... NIH (national institue of health) (federally funded) also conducts studies... in this case there was research funded by federal government and FDA in their review of the study data identified safety issues

Substantial Equivalence

If, in comparison with a predicate device, a new device is established to be at least as safe and effective. Substantial equivalence requires the new devices to have the same intended use as the predicate device and: -have the same tech characteristics, or -different tech characteristics that do not raise questions of safety and effectiveness and evidence that the new device is as safe and effective as the predicate device

ICF IC

Informed Consent Form: key document for patient - outlines obligations, what they're agreeing to, risks, and potential benefits if they participate in the trial should be understood by SIXTH GRADE EDUCATION LEVEL most important document that subjects are involved with - strategy set up for subjects to be contacted and invited to come in for an educational program Must be: - written and signed - dated (to know when it started and when they gave permission) - witnessed (different states/countries have different ways of identifying whether there was a witness or not... some places require witness sign the form, but not a universal requirement. Monitor (reviewing consents) must know what the regulatory requirements are for the agency) ** ASSENT (used for children...principal investigator talks about responsibilities are and would the child like to participate... some places allow children to sign) CONSENT Of guardian and ASSENT must be obtained in some places Informed consent: A process by which a subject, or legally authorized representative, voluntarily confirms his or her willingness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the subject's decision to participate. Informed consent is documented by means of a written, signed, and dated informed consent form. The informed consent form should be easily understood and written in lay language. In addition, each page of the consent will be dated and initialed by the subject or the legally authorized representative. challenges - length of ICs site may also create videos and identify obligations/responsiblities in summarized fashion (provides additional means for decision making) must be set up so there is NO COERCION with the patient - they should not feel like they're being forced. must be given time to consider all options and for all questions to be answered

IRB/EC

Institutional Review Board/ (Independent) Ethics Committee (noted more outside US/globally) Key purpose: protect the rights and welfare of research subjects (review and monitor the clinical research study, stay totally objective) depends on what country has the oversight and protection of patients the group is NEUTRAL they review the data, and the requirements of the study to ensure that the patient is safe and that there is no bias or coercion/persuasion in the study. an independent body constituted of medical, scientific, and nonscientific members, whose responsibility it is to ensure the protection of the rights, safety, and well-being of human subjects involved in a trial by, among other things, reviewing, approving, and providing continuing review of trials, of protocols and amendments, and of the methods and material to be used in obtaining and documenting informed consent of the trial subjects Any board, committee, or group formally designated by an institution to review, approve, and conduct periodic review of biomedical research involving human subjects. They are independent, neutral, and objective. Accountability to the regulatory agencies to insure that trials are conducted with highest standard of ethics, integrity, and so rights of participants are maintained. "appropriately constituted group formally designed to review and monitor biomedical research involving human subjects" -at least 5 members with varying backgrounds to promote complete and adequate review of research activities (must be odd number) -males and females of various races and cultural backgrounds -one scientific member -at least one non-scientific (lawyer, clergy) -at least one must be a layperson/community member with no direct affiliation to institution performing the research responsibilities: - protect subjects rights and welfare - review of research, trial's protocol, informed consent, IB, and study site's advertisements - asks for summary report from site to review (review of trial no less than once per year) - prompt reporting of trial's significant problems to its institution IRB Process: -Voting criteria (quarum of those present, proxy representation) -Authority (approve/disapprove research, request modifications in research... ultimate decision maker for particular site) -Types of reviews: full review (disapprove research), expedited review -Documents requiring approval (protocol, protocol amendments, informed consent form and schedule of subject payments, educational materials for subjects, advertisements used to recruit subjects) -Documents Reviewed: Investigator's brochure, Investigator's qualifications, sample case report forms, study grants

Device

Instrument or in vitro reagent intended for: diagnosis, cure, mitigation, treatment, prevention of disease OR intended to affect the structure or any function o the body by neither chemistry nor metabolism

Principals of ICH and CGP

International Congress of Harmonization (ICH) Good Clinical Practice (GCP) -Before a trial is initiated, foreseeable risks and inconveniences would be weighed against the anticipated benefit for the individual trial subject and society -Trial should be initiated and continue only if the anticipated benefits outweigh the risks -The rights, safety, and well-being of the trial subjects are the most important consideration and should prevail over interests of science and society -All available non-clinical and clinical info on the investigational product is adequate to support the proposed clinical trial and that the data is valid and reliable. -clinical trial should be scientifically sound, and described in clear/detailed way -Trial should be conducted in compliance with protocol that is reviewed by IRB/IC in favorable way -medical care/decisions made done by qualified physician or dentist -each individual involved in conducting trial should be qualified by education, training, and experience -all pts given opportunity and carried out freely given informed consent prior to participation -clinical trial info should be recorded, handled, and stored in a way that allows for accurate reporting, interpretation, and verification -confidentiality of records that could identify subjects should be protected -investigational product manufactured, handled, stored, with GMP and approved protocol -systems with procedure should be assured of high quality level and tested for reliability

IND

Investigational New Drug What a sponsor submits when they wish to begin work on an investigational product. An application directed to the FDA for permission to evaluate a drug (new or old) for a new indication in humans. May be a new drug with no approval yet. Report describes safety and/or efficacy of the drug, as tested in-vitro, in animals, possibly in human volunteers, and in the patient population to be investigated. Allows lawful interstate shipping of clinical supplies for the purpose of conducting investigations. Complete compilation of data to justify experimental activity in humans. Stays open unless sponsor decides to close it or major safety risk. Regulatory body very interested in what is the progress of the clinical trial. Once IND open, requires ongoing reporting of outcomes. Update usually annual and potential periodic reporting/amendments as new data emerges. When sponsor submits IND, 30 day waiting period follows. If sponsor does not hear back after 30 days, assumption is made that they can proceed with conduct of trial. IND may be opened at any point in a clinical study phase. remains open during development program and beyond NDA submission. On inactive status if development program is suspended long-term, stopped or sponsor inactivates IND (Or withdraws). If inactivated, no IND annual reports have to be submitted to FDA. IND can be terminated by the FDA if no activity after 5 years When to file IND? -file whenever clinical studies are initiated -new drug or biologic in the US -new indication or different route of administration of an already approved drug When is IND not required? -marketed drugs using approved dosage/indication format -does not support significant labeling or advertising change -route of admin. or dose strength does not put subjects at more risk than what's already on the market -In-vitro studies or studies in animals -certain bio availability bio equivalence studies -Complies with IRB review requirements and informed consent regulations -complies with regulations for promotion and sale of drugs (does not intend to invoke 21 CFR 50.24 (i.e. informed consent not required for emergency research))

IB/IDB/CIB

Investigator's Brochure Investigator Drug Brochure Clinical Investigator's Brochure a brochure that provides a synopsis, a summary and a comprehensive approach to the information that is known about the drug -chemical structure -any info from prior studies (even from animal trials) **updated on a regular basis (minimum of yearly basis... depends on phase of study) Investigators and supportive staff at site need to understand what the investigational product is, and any prior work with results that has come forth from that research. These results are shown in IB/IDB/CIB (all one in the same) - a binder that is a compilation of the clinical and nonclinical data on the investigational product(s) which is relevant to the study of the investigational product(s) in human subjects. Study staff are working in semi blind environment where a lot about how the product will work is not even known by the sponsor, and the site staff are responsible for the safety of patients and their medical treatment. Site and ethics committee members read and review so they know everything about the product that the sponsor knows

Monitor Responsibilities

Key in ensuring that study is carried out to expectation of regulatory body - at study start, make sure investigator understands all obligations - ensure investigator has proper facilities/equipment/space/capabilities - Once study started, carry out periodic visits to the site to make sure investigator and staff fulfilling investigations - review subjects records - make sure staff is follow up with participant drop outs and did they come back for final visit

CDER division technical discipline: Project Management Staff or Consumer Safety Officer

Look across the various disciplines, bring together questions, coordinate responses from the sponsor to be sent back to the various organizations. critical to the application review process, make sure that the process is moving effectively and expeditiously. The voice from the FDA to the drug sponsor. Ask questions and give feedback to the sponsor about what is happening during evaluation of the drug product. After an IND or NDA is submitted, project manager is assigned. Sponsor notified contact info for the project manager and role/responsibility description. Has expertise about the drug review process and the policies, procedures, and idiosyncrasies of their respective divisions.

Site Management

Look at it like the piece of a puzzle coming together... considering each piece and how it represents individuals within the site and those the site touches

Overall IND structure

Modular Structure of Common Technical Document: (IND= common technical document) module 1: administrative and prescribing information (not harmonized) module 2: the major portion of IND and incorporates data already collected from both non-clinical and clinical sites modules 3,4,5: much more focus on data level results that had been collected vs. module 2 majority of those results had been summarized

GLP Equipment Design

Must be: -appropriate and adequate capacity to function per protocol -suitably located for operation, inspection, cleaning/maintenance -adequately tested, calibrated, and/or standardized

Composition/Function/Operations of IRB/IEC

Must have written operating procedures, maintain written records of its activities, including meeting minutes; and should comply with GCP and applicable regulatory requirements Must make decisions with at least a quorum present (include who participated in decision making process - if IRB member is also a PI, they can not make decisions regarding their study)

NDA

New Drug Application submitted to FDA. approval required by law for interstate distributions of drugs and antibiotics. -complete compilation of data to justify approval for use in humans (based on a drug that is efficacious and a drug that is safe) -draws the line as to what the product is and its intended use - any deviation lends product to adulteration or misbranding -investigators discover additional benefit (may become separate indication) -approval would be for only the initial indication (violation of the law) -approved package insert (PI) or "label" must accompany all shipments PURPOSE - provide documented evidence of efficacy, safety, quality, and mechanism for drug approval

OHRP

Office for Human Research Protections looking out for the protection of patients (many agencies/regulatory bodies that do this)

CDER division technical discipline: Pharmacology

Pharmacologists and toxicologists evaluate the results of the animal studies in attempting to relate non-clinical drug effects to potential effects in humans. Pre clinical - animal studies could show teratogenic effects or high risk of development of cancerous type side effect. Pharmacologists and Toxicologists are critical for evaluating whethere things should be introduced to humans. Microbiology - evaluates products effects on viruses or other microorganisms

Pre study Site VIsit (PSSV)

Pre Study Site Visit -monitor or CRA investigates whether or not a site is appropriate for a study -study team must be identified and their roles and responsibilities outlined -sites need to understand who to contact for any of their needs, as well as reporting requirements -study team is the key cross functional group that drafts the protocol -fact-finding visit! monitor must be objective (ask questions, gather info for analysis at a future time) -not a regulatory requirement... but is something that every sponsor agency usually carries out First... (prior to pre study site visit) -monitor and study team create a feasibility questionnaire that identifies major criteria for site selection -sites decide whether or not they can meet requirements -confidentiality agreement must be signed between sponsor and site personnel before sharing info about protocol/product -once agreement signed, investigative brochure and either site protocol or synopsis is sent to the site -site decides if they're interested

Clinical Trials Phase Review

Pre-clinical: chemicals and potential rodents Clinical - phase 1 (volunteers) - or sometimes certain therapeutic areas may be patients (oncology) Clinical - phase II: introduction into patients (small number of patients) Clinical - phase III: large numbers of patient and long term study of product FDA Registration: registration of product goes to FDA Launch: If approval, marketing organization brings forward a launch. Advantages of product made known to population. Post-Launch: Might be more interest in finding new implications and ongoing safety parameter to ensure no further issues. Summary - compound/device identified, testing in animals and evaluate what area in the body the drug targets, human research, once enough data obtained move into marketing/FDA, product launched, patients followed closely, patent filed so other companies don't develop same product, patent life runs out at some point (ex: 20 years) so product needs to be launched quickly so sponsor can get their money back. Dosing/manufacturing may be edited to increase compliance for patients.

PI

Principal Investigator (aka clinical investigator or sub investigator) key person held accountable for the conduct of a study at their site Guidelines: - expertise in both clinical research and in the therapeutic area being studied (accountability to IRB or Ethics Committee AND sponsor) - sign a contract or agreement with the sponsor and follow through - provide adequate resources (numbers and expertise) so participants rights are met - ongoing communication with IRB - compliant with study protocol - handling of the trial product (i.e. locked a certain way and how its dispensed) -"unblinding" if needed after adverse event (who was on placebo vs. real thing) - provide informed consent to patients - answer participant questions - ensure reports and records are maintainted to highest quality/sent to IRB or EC if needed - communicate safety information in timely manner (sponsor then may communicate to regulatory agency) - communication if there needs to be a premature termination of study - if there is compensation, ensure its not coercion

Randomization

Randomization plan - the process of assigning trial subjects to treatment or control groups using an element of chance to determine the assignments in order to reduce bias. Reliable, valid, and non-bias data is the goal. When the team sets up the process, it is placed within the protocol.

GLP Records and Reporting

Reports typically include: - summary - testing methods - results - conclusions of a study - all raw documentation - protocols - certain specimen generated during non clinical study

Ivestigator

Responsible for the conduct of the research study at a trial site. If a trial is conducted by a team of individuals at a trial site, the investigator is the responsible leader of the team and may be called the PI. Sub Investigators - when there are more people supporting the PI

Responsibilities of IRB

Safe guard the right, safety, and well being of trial subjects. That is what provides them with the obligation of objectivity, being comprehensively informed, and challenging areas they are reviewing if the right, safety and well being of trial subjects is potentially not being maintained. Receive from sponsor certain documents... -protocol (the scientific medical bible in which the study staff must conduct the trial at their site)... If updated in the form of an amendment, IRB must review it. Make sure its ethical, within standard of care... is risk balanced out with potential benefit? -informed consent - ensure that it is comprehensive, ties in with what is asked in the protocol, and that the rights/privacy, alternative therapies, safety protection all included (Ensure that these documents are available and provided to the participants. So if they have questions/concerns at any time, they can refer back to informed consent.) -Investigative brochure - comprehensive and in depth document provides to the study staff and IRB and EC an understanding of what the sponsor knows to date about their products. Identifies areas of risk and adverse experiences that have already been shown through prior research. Identifies chemical composition/device composition that may have an impact on the participants. -Curriculum Vitae of staff must be provided to IRB Ensure that study staff qualifications tie in with the protocol, purpose, objective, and the right of the participant to be provided safe and qualified care during the study. Sponsors will sometimes provide minimal reimbursement to participants (ex: for transportation). IRB makes sure that participants don't feel a sense of coercion by this reimbursement... IRB reviews advertisements on social media and other platforms... make sure they are comprehensive and not promising anything to participants that is not already known. REVIEW PROPOSED CLINICAL TRIAL: -Document views in writing -May have approval/favorable opinion -Tentative approval with some modifications requested and/or required -Disapprove a trial or informed consent template bc they feel it is not meeting the GCP/ICH guidelines for quality and protection of participants Things change as study progresses... new info received... updates are provided to IRB or EC. Ongoing obligation to review any documents submitted to them with regards to the study. They may terminate or suspend their prior approval or favorable opinion at any time.

SAE

Serious Adverse Event Serious Adverse Drug Experience (ADE, ADR, or SAE) Any experience or untoward medical occurrence occurring in a research study subject that at any dose results in death, is life-threatening requiring hospitalization or prolongation of hospitalization, results in a persistent or significant disability or incapacity, or causes congenital anomaly.

SR

Significant Risk either the patient is at significant risk for injury or the study itself may be at significant risk to have patients for the future experience injury

SIV Initiation Meeting

Site Initiation Visit After all regulatory and contractual agreements have been finalized, the sponsor and invesetigational site personnel will review in depth the protocol implementation (includes how to dispense the drug, what patients are eligible, how to handle AE reporting). Conducted by the monitoring staff. Assurance that there is a signed study agreement in place. (many meetings take place between the sponsor and the site staff) investigator meeting may substitute for SIV. -new CVs may need to be collected -sponsor can re-identify the requirements listed under protocol. and the key scientific and medical principles backing this. -NOT MANDATED by regulatory agency -review background of study/pharma of the drug -inclusion/exclusion criteria -what other medications can be included/excluded (to avoid safety issues) -review of how efficacy is evaluated -procedure for discontinued patients ("due diligence" to identify whether a patient is safe... documentation!) -local vs. central lab (always good to have local as a backup) -quality of lab/lab ranges -MOST IMPORTANTLY: code break procedures...what drugs/placebos to use for intervention if needed -destruction procedure for end of study Objectives: -instruct each team member of the protocol requirements -roles, responsibilities, accountability of each of the site personnel must be emphasized (understanding that PI still holds ultimate responsibility) which he signed for when submitted 1572 -gives monitor another chance to tour the facilities and assess if anything has changed/are they moving? appropriate temp control? adequate supplies? -another review that all regulatory documents have been collected and submitted with approval to IRB/EC -check appropriate inventory of the device/drug -monitor reviews what their future role will be with the site during conduct of the study (primary contact for any questions) RED FLAGS: -key staff not present -no posed questions -lack of knowledge of protocol -missing documents -inaccurate inventories **needs follow up through an initiation visit report generated by monitor (same as PSV)

Supplies and Investigational materials

Site management - supplies and materials: 1. Investigational product: controlled substance or device, need to provide oversight more so than regular OTC drugs. done through inventory log. Site makes sure that product is locked and in appropriate environment/temp 2. Accountability Logs: inventory logs up to date, make sense, logical/comprehensive/complete 3. Return of materials: discussion of when this will occur, mutual discussion between site and monitor 4. Lab supplies: sponsors are very generous - if labs being done offsite, there will not be as much inventory. Many times whats sent is a packet (means for less error by site staff) 5. Case Report Forms: (may still be paper, mostly electronic now) 6. Administrative Binders: mostly in paper form, future may be electronic 7. Tech supplies: laptops provided by sponsor? electrocardiogram machines? space needs to be allocated/security provided

Pre Screening

Sometimes study staff needs to look at database of patients and determine which study might be most appropriate for potential participation. Procedures that are performed as part of the standard of care - such as diagnosis of or treatment for medical condition - procedures may be performed and then subsequently used for developing eligibility without consent. Done to provide a standard medical treatment plan for a patient experiencing a medical problem.

Sample IRB Membership LIst

St. Mary's Hospital Boston, MA 19000 Institutional Review Board (IRB) IRB Members; Joseph Summer, MD, Chairman (5 names) Membership List - January 2007 to January 2008 (list of names and titles)

SOP

Standard Operating Procedure used not only in the clinical trials arena, but in most companies - defines how people work Detailed, written instructions to achieve uniformity of the performance of a specific function Utilized by sponsor as well as the site. SOPs created at the site that all staff follow, and SOPs that a sponsor has that are consistently followed to ensure reliability and validity.

What about the study? (schedule and site selection)

Study Schedule: -are we a "rescue site"? (bring people in at the last minute to help complete on time) -why is rescue needed? -where is study currently? still in planning stages? perhaps protocol is not completed? -is it an "orphan drug" status project? could be risk for site to commit... Site Selection: -best foot forward - make a great impression -highlight all capabilities -showcase the facilities -never say NO - if you don't have something, show willingness to obtain or learn if necessary for protocol -have regulatory info available -convey "busyness" but make enough time to spend with them to make a decision

STV

Study Termination Visit close out visit last official visit in which a monitor will go to a site and evaluate that all the completed activities are accurate, logical and complete

Protocol

Study staff must understand and be very knowledgeable of A key document that describes the objective(s), design, methodology, statistical considerations, and organization of a research study. The protocol usually also gives the background and rationale for the research study, but these could be provided more in depth in other protocol referenced documents. Throughout the ICH GCP Guideline, the term protocol refers to protocols and protocol amendments. IDENTIFIED ELEMENTS: - general info about the therapeutic area of the product - background info - objective identified, and a purpose (what the outcome should be) - the design - appropriate subjects and how to select - reasons for withdrawal - treatments subjects will be receiving - data that will be collected/what results would be important - efficacy (does the product work?) - safety (is there risk to patient population?) - how results will be analyzed statistically - administrative portion (what source documentation will be reviewed and what quality control will be implemented to assure data is credible) - how data will be handled/records kept - intent of trial being conducted ethically - any additional costs - publication policy for this particular site and within the study - any supplements or addendum that may help investigator understand how to run the study scientific/medical document that sets out both from science, medicine and operationally, what the patient will go through Can be updated through AMENDMENTS

Sub-I

Sub-Investigator a highly qualified individual who is supporting the work of the PI Any individual member of the research study team designated and supervised by the investigator at a trial site to perform any trial-related procedures and/or to make important trial-related decisions. (e.g., associates, residents, research fellows, interns, or physicians taking a secondary role in the study... maybe under mentor ship of PI)

CDER division clinical discipline: Medical/Clinical (Medical Officer)

Takes the lead role in IND/NDA reviews and reconciles results of other discipline reviews. Responsible for reviewing clinical sections of submissions (e.g. safety of clinical protocols - IND; results of clinical testing - NDA) Primarily physicians and experts in their therapeutic areas. However, sometimes non-physicians (dentist, psychologist, PHD... for either psychiatric or dental product being evaluated)

IRB Composition

The IRB is composed of a reasonable number of members (diverse group, but not TOO many people) who collectively have the experience to review and evaluate the science, medical aspects, and ethics of the proposed trial. Group must be OBJECTIVE - at least 5 members (GCP/ICH guideline recommendation) (odd number so there will not be a tie when votes go on and decisions are made) - should be at least 1 member whose primary area is nonscientific (doesn't mean they won't have any background of science... they just need a broader view of things) - there should be at least 1 member who is independent of the institution/trial site (to minimize/prevent pressure to agree to a study due to compensation) - there should be gender diversity (different points of view)

Sponsors and Sites Goals & Priorities

The Sponsor: 1. get drug to market -not just because profitable... intent is to be able to present another option to patients who need help 2. ensure patient safety (main goal!) 3. meet/exceed standards -at least equivalent or superior to current standard that exists 4. offer efficiency -sponsor is not gaining product unless its out on the market -enhance speed (least amount of time to get drug out there) 5. make a marketing splash -commercial advertisements -ex: purple pill (nexium) The Site's Goals: 1. Get drug to patient 2. ensure patient safety 3. maintain reputation (ex: yale, harvard, stanford...) 4. remain fiscally sound (solid budget to continue doing research) 5. offer experience for doctors 6. align with mission (mission of the institution) Site v Sponsor -sometimes they have different priorities (ex: sponsor cares more about time) -80% clinical trials delayed at least one month due to unfilled enrollment -screening can be more time-consuming than anticipated -want to go slow to get used to drug/procedures

Procedures of IRB

The following procedures upon establishment must be documented in writing: - composition and authority under which established - scheduling, notifying its members of, and conducting its meetings - conducting initial/continuing review of trial **IRB communicates to principal investigator what the requirements are... it is the investigator's obligations to meet those requirements** Procedures must identify... - frequency of continuing review that IRB expects from study staff or sponsor and obligations for continuing review (usually MINIMUM of yearly updates) depends upon duration of study (ex: phase one are short term... requirements may be for each tier of patients that their data be submitted for review before next group of patients enter) - process for expedited review (usually only for minor changes of protocol) rights of participants are what's being maintained by EC, so quick turnarounds usually not excepted... must be enough time to review/evaluate large amounts of date (ex: minor changes like phone number in protocol could be expedited) **NO PARTICIPANTS ARE TO BE SUBMITTED TO A TRIAL BEFORE IRB/EC PROVIDES WRITTEN APPROVAL, NOT JUST VERBAL** (sponsor must receive that documentation before device/drug released to site) Since IRB has the responsibility of the approval of protocol and informed consent - there should be no change to protocol or informed consent UNLESS approval from IRB first. Sometimes, monitor will go to site and see that study staff member has not followed a procedure identified in protocol... considered a protocol deviation... most IRBs will need to be informed of the violoation. Consider IRB/EC to be the BOSS of the study site. If study team at trial site is not following recommendations, they can terminate rights of PI to continue the study Investigator should proptly report to IRB: - any deviations/changes of protocol to eliminate immediate hazards (want to know what the hazards are and what changes have been implemented to prevent harm to future subjects) - changes increasing risk to subjects and/or significantly affecting conduct of trial (IRB will not be surprised that risk may increase... but they want to know what changes are made to eliminate risk/harm) - all serious and unexpected adverse drug reactions - new info that may adversely affect the safety of the subjects or the conduct of the trial **brochure will be updated by sponsor and provided to IRB - should show accumulation of data that has been collected since initial review - will give IRB more information for which they should base decisions regarding progress of study or potential suspension of study

Investigator's Meeting

The purpose of the meeting is to learn about the research study in detail and to clarify the protocol. Another place where the site staff may gain some knowledge about protocol/investigative product. May be face to face or virtual. Taped and sent to site so they can review material at their leisure or when certain questions come up. -post site selection -can occur electronically or face to face -generate energy, interests, and commitment among investiagors to be able to conduct the study -explain how protocol has been progressed/any new info -sponsor is a salesperson... saying "we should be your sponsor of choice"... a lot of competition for the patients -can be seen as "study initiation visit" bc in depth discussion of protocol, science, advantage, procedural info, anything needing training... -may be divided into sections -not required by regulators, but help ensure success -in the past, more elaborate -must be a reporting of meals for investigators (sunshine act) Logistics: -Appropriate timing! before study starts, but not so far in advance...) -who are the attendees? PI, sub-investigator, study coordinator, ancillary personnel -planning (usually 1-2 days long), reporting provided to site staff so they can refresh on key concepts Agenda: -rationale (site staff needs to understand why protocol is being conducted) -discuss study protocol (review all specifics) -obtain feedback and guidance from key opinion leaders (SC breakout session) -adverse event reporting -quality assurance -good clinical practices -set expectations

Electronic Patient Diary

The use of an electronic device/software for which a subject participating in a research study directly enters observations or directly responds to an evaluation checklist ex: patients asked to track their vitals or symptoms between visits gives the opportunity for the site to see what entry the patient has put in prior to the visit... does the patient understand the instructions? does the data make sense? then they can contact the patient to clarify if needed

Screening

The use of screening tests to assess whether prospective subjects are appropriate for inclusion in research study is an appropriate pre-entry activity. An investigator may discuss availability of studies and possibility of entry into a particular trial without first obtaining consent. Informed consent must be obtained prior to initiating any procedure solely for the purpose of determining eligibility for research. A site may be doing more than one study, and an investigator feels that the patient is qualified for all of them. In the best interest of the site to share information and gauge the patient's feedback. These procedures are considered part of the screening selection and recruitment process and therefore, through their documentation in the protocol, require IRB approval! Site determines how patients will go through trial and that first step of how they start in the clinical trial at the site - usually under "screening".

Biological Product/Biologic

Virus, serum, toxin, antitoxin, vaccine, blood, allergenic product, or protein (except chemically synthesized polypeptide, applicable to the prevention, treatment, or cure of a disease

Feasibility Determination

What site sponsor is looking for: -does it have scientific merit? -is it safe? are the hazards minimized? -do we have adequate patient population? -are there competing trials? -is there an interested PI? -will the IRB approve it? -is the budget adequate? -do we have the resources?

Integrating Outcomes

What type of outcomes does a site need to see will be the result of their participation in a study? -Disease progression: looking for a cure -looking at survival? (ex: chemo) -worsening outcomes diminished with product? -patient's health status -quality of life functional status -patient satisfaction with their lifestyle -cost utility analysis (this product vs something else out on the market) -more effective/less costly? **not just looking scientifically any longer, now due to mandates of the world... we are looking at a total picture of integrating these outcomes into clinical research

Simple to Complex

Why are certain sites more successful than others at handling complex protocols? Site manager... 1. Assess: assess for compliance, new AEs, concomitant meds, new meds 2. Equipment: measure height of camera, table, do angles, document times and timing 3. Efficiency: making the MD wait, doing additional procedures, filling out multiple paperwork (Physician can assign roles/group tasks) 4. Labs: use local labs or send out? need to be on ice? 5. Procedures: done by different ancillary staff (techs) - how to ensure quality? study coordinator has to figure out early on how to ensure consistency accross individuals 6. Appropriate SOPs for research study visits? more focused direction needed? Everyone participating need to understand what/when/how to do something

Clinical holds

clinical holds decision: -CDER believes subjects are or would be exposed to unreasonable risk of illness or injury, a Clinical Hold decision would be made -Sponsor must address issue and if not, the study will be delayed if not started or suspended, if ongoing -not a decision taken lightly! intent of FDA is to facilitate the approval and launch of safe/effective drugs -holds are reviewed by upper management of CDER -Hold order may only apply to 1 study or more -If study delayed, no study drug should be provided to subjects until hold released -If ongoing study, no new subjects may be entered in trial -if subjects on study drug, study drug should be removed from patient unless FDA decides that risk is lower for ongoing subjects than new patients Grounds for clinical holds: -current or proposed exposure deemed unreasonable, risk to subjects -investigators not qualified (training or experience) -IB is misleading, erroneous, or incomplete -IND does not contain sufficient info to assess risks to subjects in the study -protocol design or investigation plan is clearly deficient in meeting its stated objectives How a site avoids clinical hold? -GCP! FDA sets minimum standards for conducting clinical trials by identifying and defining responsibilities of key personnel (sponsor, investigator, monitor, and IRB) involved in clinical trials -Goal 1: to ensure the quality and integrity of the data obtained from clinical testing so that the FDA's decisions based on these data are informed and responsible -Goal 2: Protect the rights and the welfare of clinical subjects

Putting a Price on Every Patient Article

coercive event in order to recruit patients, the site provided a very high level of compensation. many patient participated even though it could have been in their best medical interest to participate in a different study or none at all

Death of Infant Article

example where informed consent had incorrect information... Typically, IRB or ethics committee responsibility to read all info and ensure what is shared with participant is accurate In this case, an infant died because what the parents agreed to and what info they had available (through the IC) was incorrect.

Laws (overview)

focused on USA... Ex-US: E.U.s directives shed light on E.U. nation's laws 5 key areas: drug and device legislation, privacy, payment transparency/gift ban laws, local sponsor requirements, anti-corruption/anti-bribery

Blinding/masking

if PURE OBJECTIVITY is needed - so bias is minimal A procedue in which one or more parties in the study are kept unaware of the treatment assignment(s). Single bliniding - usually subject(s) being unaware Double bliniding - subject(s), investigator(s), monitor, and data analysists may all be unaware of the treatment assignments

Protocol Amendments

submitted to regulatory agency include: -new protocol -changes in a protocol being conducted -new investigator information Sponsor submits new investor information at 30-day intervals (once/month)

Good data tools

what does site need to have? -study coordinator needs clear instructions -subject ID# (identification done so when data goes to sponsor, they're clear) -space for date if same form used for more than once visit (sponsor needs to be able to link it all together) -simple questions/not complex, one question at a time -definitions near questions -use drop-downs or check-boxes as much as possible (instead of typing word content data) AND easier for sponsor to interpret data -include space for explanation of "other" (for unique circumstances) -include N/A or N/D (not done) (not done appropriate if patient expired) -list range of values for any numerical answers

Data Safety Monioring Plan

what our data analysts strategize when they are reviewing the data: developed before any data is collected The purpose of this plan is to assure 1) safety of study subjects and 2) validity of the data. The essential elements of a Data Safety and Monitoring plan are: -monitoring the progress of the trial and safety of study subjects -description of the mechanism for reporting adverse events -plans for assuring data accuracy and protocol compliance