Module 2

Over the counter (OTC) products

- non-prescription - dietary supplements - neutraceuticals Regulation effective December 31, 2007 Public Law 109-462 Sec. 760 "serious AE reporting for non-prescription drugs" -serious event reporting only -15 business days -report on MedWatch 3500A

Risk Management

-an iterative process of assessing a product's benefit-risk balance -developing and implementing tools to minimize risks while preserving benefits -evaluating tool effectiveness and reassessing the benefit-risk balance -adjust, as appropriate, the risk minimization tools to improve the benefit-risk balance

What is a Suspected Adverse Reaction or Adverse Reaction?

-any AE for which there is a reasonable possibility that the drug caused it -for the purposes of IND safety reporting, "reasonable possibility" means there is evidence to suggest a causal relationship between the drug and the AE -"suspected AE" implies a lesser degree of certainty about causality than "AE" Important note - AEs are differentiated by "reasonable possibility"

Site discussion with the monitor

-ask how other sites are successful, different screening strategies, novel source documents, suggestions for staff education, etc -ask about subtle issues not covered in protocol: do you re-dispense unused drug at each visit? Can a visit be done on a weekend or holiday if have send out labs?

Partner pregnancy

-protocols from the sponsor with certain agents will require some sort of disclosure to male subject's female sexual partners about the potential risk of pregnancy -the sponsor may ask/include in the protocol that if the female partner becomes pregnant during the study and the subject is receiving the agent, she will be asked to consider allowing the sponsor to collect data on her pregnancy and/or its outcomes

Study protocol

-provides instructions on reporting safety data -provides details on time frame for reporting -describes event collection (starts with informed consent or randomization concludes 30 days or 5 half lives (whichever is longer) after last dose or study discontinuation) -define any nuances with respect to hospitalization -denotes adverse events of special interest that may be collected during the trail

What is REMS?

A formal Risk Evaluation and Mitigation Strategy FDA may require the sponsor to develop a REMS in order to ensure that the benefits of a drug outweigh its risks May be required at the time of submission May also be required based on "new safety information" received post-marketing FDA and REMS: -over 240 products have had or currently have a REMS (July 2015)

Benefit to risk ratio

Benefit: -efficacy in treating a particular disease Risk: -reasonable safety in patient population being treated for the indication being studied Benefit - Risk acceptable ratio from company, physician, and patient perspective

Success factors

Three success factors (takeaways) in dealing with data management activities: 1. clear communication and documentation (in all phases of CT) 2. data quality (deliver an accurate representation of what's really happening in the clinical trial) 3. efficiency/faster drugs to help patients (right drugs to the right patients at the right time)

What is data management?

process of reviewing and managing collection of data

Personal Data

any information related to a research subject, which can lead to the identification, either directly or indirectly, of that subject

Data management activities

continues to evolve! 1. set up phase 2. maintenance phase 3. database closure

completion of a MedWatch report (class exercise was to print instructions and form)

https://www.fda.gov/safety/medwatch-forms-fda-safety-reporting/instructions-completing-form-fda-3500#Section%20A:%20Patient%20Information

Adverse event reporting process

investigator reports event > sponsor codes the report > sponsor assesses the event: serious? causality? expectedness? > sponsor reports the event to the regulatory agency > sponsor sends SUSARs to investigator for awareness > where applicable, sponsor evaluates and updates relevant reference materials

limitations of spontaneous reports

passive surveilance! under reporting can occur and is variable from drug to: -reporting bias -quality of reported information -duplicate reporting -can't reliably estimate the incidence rates of events - numerator uncertain, denominator can only be projected

Part II MAINTENANCE PHASE

purpose: assure accurate, reliable, complete data data validation activities: receiving, entering, cleaning, coding, reconciling, and transferring data goal: ensure that the quality data is available for analysis at the end of a study when the data is received it is entered into the clinical database by the site personnel and it is validated by the data management experts on the clinical study team

Third Party Vendor Data

third party data: collected outside of what is included on the CRF -data additional to CRFs info is collected -to speed up process of standardizing equipment, sponsors use centralized vendor -external data can originate from different sources: LAB, PK, IVRS, ECG, IMAGES external vendors> IVRS/CENTRAL LAB 1/ CENTRAL LAB 2 (e.g. imaging)> clinical trial study management system>clinical database

Data validation: critical variables

"critical variables" are the data points most important for the study that need to be considered 1. define a list of critical variables 2. address the purpose, characteristics and complexity of study in the data cleaning procedures 3. monitor data validation production functions 4. provide CRF completion/data entry instructions and helpful tips: -to follow a patient's progression -to predict the last patient's last visit dates 5. expected visit date reports can be programmed into most reporting and tracking systems (to support validation of the data)

Measuring quality data (part II maintenance phase)

(QC measures to ensure quality must be in place in addition to on-going validation of the data) 10% for a partial QC and 100% for full QC (should be done both prior to locking the database and after locking it as well) -use quantitative methods to measure data quality -use standard processes for each trial. familiar, controlled, and understood processes prevent errors -use statistically appropriate inspection samples for decision making **if a MANUAL QC is put in place instead of a quantitative one, the method of review should be stated in the clinical study report, otherwise known as the CSR

Endpoint Adjudication Committees

(aka clinical event committees) -determine whether the endpoints meet protocol specified criteria (info reviewed on each endpoint may include lab, path, imaging, autopsie reports... any other data deemed relevant) -committees usually masked (even when study unblinded)

Vaccine reporting

(spontaneous unsolicited reporting) **as complexity increases, more important to pay attention to safety measures** -begins after market approval -FDA has a unique vaccine reporting system to detect possible signals of AEs associated with vaccines subsequent to market approval

Redundancy of data in CRF

**Another very important thing to avoid when designing a CRF is redundancy of data -redundancy of data can be used to assess data validity in cases where other means are not practical -data based on the same measurement should not be collected more than once or in more than one place -the raw data or the calculation based on raw data should be collected but NOT BOTH (ex: if age is programmatically calculated based on birth date, there should not be an enterable field for age also) -RAW DATA is generally preferable for example: "ethnicity" is captured on the demography form, and if it was captured on another form like physical exam, it could be documented slightly differently. This would cause a need for additional reconciliation between forms and raise the potential for error in documenting an answer in different ways!

Monitor Communication

**appropriately communicate with site to either say good job or clarify any issues ways to communicate: -sit down with study staff at end of site visit (give report card) -correspondence (so there's an assurance that everyone received face to face message) -trip report (monitor creates and it is maintained in central location at the sponsor.... study team has access so they understand each site's performance)

How site prepares for monitor visit

-Check that CRFs are complete -request for source documents to be available from medical records (takes all day to gather) -have all questions ready (about protocol, screening...) -confirm coordinator and PI are available -schedule clinical pharmacist to show the drug -schedule procedural area if device is stored there -confirm what exactly the monitor will be reviewing at site (which enrolled patients, screen fails, IRB documents, other reg docs) -Order medical records if necessary in time to receive prior to visit -make sure patient charts are in order, paperwork in folders, labs evaluated -Find a place for the monitor to work all day - near you and far from noise - may need computer, fax, scanner, copier, phone... -be available throughout the visit for questions or to obtain documents -reserve time at end of visit to go over findings - these can take several hours! FINAL CHECKLIST: -all data entries written legibly -keep detailed notes in source documents - especially about the protocol proceedings - consent process, any outcomes measured -organize sources with CRFs for presentation to monitor -be accepting of monitors requests -have accurate, up to date logs of any investigational products -keep your PI up to date

FDAAA

-Congress approved the FDA Amendments Act (FDAAA) effective march 2008 -control drug marketing and labeling require post approval studies -establish active surveillance systems -more visible to the public -A key provision allows FDA to require a Risk Evaluation and Mitigation Strategy (REMS) for drugs associated with greater safety risks -FDAAA's passage included: Reauthorization of The Prescription Drug User Fee Program (PDUFA) that expired Sept 30, 2007

Site's Study File (administrative binder)

-Correspondence (monitor should receive prior) -supplies (forms that site personnel needs to fill out when supplies are sent to them) -monitoring log (monitor signs in each day that they are at the site and what they're there for) -regulatory/ethical documents (protocol, amendments, ethics committee approvals, advertising, potential reimbursement offered to pt- make sure not coercion!)

Key process that monitors follow when they go to a site

-ENROLLMENT: monitor should see how many pts have entered/how much data entered (by looking at CRF)... did they adhere to protocol? any AEs? receiving adequate doses? -FILES: may not need to look at every visit... depends on SOPs of sponsor, how frequently monitor is at the site, and how frequently there are changes to regulatory file -FACILITIES: any changes to the location? are they in compliance with regulations? any new staff members? appropriate training? Follow up to any gaps that monitor has noticed

signal methodologies

-ICSR review -aggregate data review -FOI data review -software: flexible search tools and integrated reports provide extensive trending and visual representation of key performance indicators related to product safety risk -data mining

Privacy Protection Afforded to Research Subjects

-Protocol review and approval by an IRB -Right to informed consent -Right of the subject to withdraw consent -Right to notice of disclosure -Confidential collection and submission of data **Complete anonymity is not practical, but information should be safeguarded to the greatest extent possible Patients are identified by an ENROLLMENT NUMBER instead of their name to further protect them

After a monitoring visit

-SOON after visit, review all notes, issues that need resolution -Correct CRFs if needed -Create/modify new processes for improved data handling (have PI sign off on them) -Orient new staff (use training materials shared) -Send monitoring report to IRB

Monitoring Report

-Submission: monitor should submit written report to sponsor after each visit (or interim communications that are trial related/significant) -Demographics: date, site, who monitor and investigator is -Summary: what monitor reviewed, significant findings, actions taken from output of the visit -Review: someone who looks at this report, reviews, and ensures that there's follow up

SUMMARY (what study coordinator needs from monitoring visit)

-Verify understanding and correct format of documentation -Discuss protocol details (especially enrollment issues) -Ensure sponsor contacts available for questions -Discuss operational issues and investigator obligations (make sure she knows how to get a hold of site team)

Signal Detection and Trending

-a "signal" is a potential safety issue (safety signal) will be further evaluated and possibly monitored -regulatory agencies expect bio pharmaceutical companies to have ongoing safety signaling or surveillance programs -utilize all sources of potential signaling data -provide periodic analyzed information for incorporation into surveillance documents (such as PSURs, DSURs) -ongoing throughout a product's life cycle

General Monitoring Guidelines

-accurate visit dates and appropriate scheduling -dosing schedule and compliance -adverse events -study procedures being followed -complete/consistent source documentation -periodic review of study files determined on how often monitoring visit occurs/how often there are additions to the files (determined through site and study)

Third party vendor data

-audit external data providers regularly -enforce a formal data clarification process for handling data discrepancies and data updates -provide vendor-specific training. A clear understanding of what is expected by both sides is critical for quality and efficient conduct of the clinical research Primary Key Variables (protocol subject identifiers): -sponsor name/ID -study/protocol ID (any combination of project and protocol) -site/investigator ID -subject identifier (subject number, screening number or number assigned by the CRF used) -Clinical event ID (visit number) -sample ID (vendor or device specific sample identifier or a subject visit) Secondary Key Variables (additional identifiers) -gender -DOB -initials -transmission data/time -date associated with the subject visit -sequence number (when more than one observation per record exists) For quality and speed, errors must be eliminated at the source or as close to the source as possible! Editing and verification procedures should include: -provisions for treatment of partial data -checking for duplicated demographic details -subject numbers allocated for the study or investigator or both -treatment codes allocated per study or investigator or both -Problems with transmission of data will result in data being lost or loaded incorrectly -Any data transferred must contain sufficient info to be uniquely linked to the source of the data -Public encryption mechanisms are recommended for use when transferring data via the Internet -Use password-protected files such as ZIP archives or dial up FTP transfer if use of encryption software is not allowed the SPONSOR Is ultimately responsible for the quality and integrity of the trial data (refer to FDA guidance for additional info about industry, computer systems used in clinical trials)

Discuss with study staff prior to close out of a study

-close out activities and what is expected of the site during this time -audit concerns (site should always be audit ready! total compliance in procedures...) -available to answer questions or concerns that site personnel may have

Site requirements for monitoring visit

-complete case report forms (so they can be reviewed and trends can be determined) -source documentation (so monitor can compare source documentation to data uploaded to CRF) **collect notes when patients are there -provide large enough space with support for monitor while she's there -personnel availability

Site administrative requirements: STUDY FILE

-correspondence? phone log (all convos with monitor/study team) -supplies/re-order info -monitoring log (have it out on table so its available for monitor to sign) -regulatory/ethical documents (everything back from IRB and signed off?) -financial records (move to another part of filing system so budget people have access to it without digging through other documents)

Case Report Forms - eCRFs

-could be paper or electronic -can be collected manually, using systems, the internet, voice response systems, or even touch screens -any changes made to a CRF have an audit trail associated with it to ensure that all original and modified data is tracked for review purposes **Note "permanent" in the context of these definitions implies that any changes made to the electronic data are recorded via an audit trail MOST IMPORTANT DOCUMENT (exception of the protocol) -instrument in which data is collected and needs to accurately follow the design of a trial (data will show efficacy or lack of efficacy in a study drug) -designed to capture data within several different methods... paper or electronic medical records, forms at the clinical sites, voice response systems, in addition to electronic systems that transfer data from outside vendors such as laboratories

Data validation (once completed)

-data may be changed as a result of data cleaning procedures -data changes should be recorded and documented by original site signature acknowledging the new data -data cleaning conventions (e.g. self-evident) may specify data that can be modified without a site's acknowledgement -an audit trail should reflect all deletions, updates or additions to data after initial entry -if any telephone conversations with the site are utilized to authorize data changes, these changes should be documented by both parties

Pregnancy reporting

-effective contraception must be used during clinical trials (rarely pregnant women are used) -typically many product labs have contraindication labels -all reports of pregnancy should be captured to provide a database of exposure -all pregnancy reports should be followed up at the time of the report and at the outcome reporting AEs to regulatory agencies: -general rule: any miscarriage also referred to as spontaneous abortion would be reported as SAE -pregnancy registries: known teratogen, at risk patient population, unknown effect in pregnancy

Example eCRF

-form fields and controls -enterable fields and questions with check boxes -AE form: (symptom, onset date, continuing? end date, relationship, outcome...)

Expectedness

-has this event been seen previously and with the same specificity or severity? -Investigator brochure (pre-marketing) greater severity, e.g. if IB states increase LFTs and event is hepatic failure -package labeling (for marketed product) core safety label

Who is the monitor?

-held accountable for the review of data at a site, and that all policies and procedures are being followed, and the patients are safe -has to be flexible, work very hard

What goes into a SAE report?

-identification of case (country, report type, etc) -manufacturer received date (awareness date) -primary source of info -info on sender and receiver -patient characteristics (demographics, PMH) -reactions/events (medDRA coding) -test results, concomitant medications (WHO drug) -case narrative

Unbinding

-in general FDA does not require unblinding of investigational drug (placebo or comparator trial) for regulatory submission of an event -investigator may request that the treatment arm be unblinded in order to treat the patient's AE -the sponsor should have a defined process for unblinding and it may include personnel involved in safety -however, it is important to ensure that the clinical study team remains unblinded to avoid introducing the potential for bias

Ema Risk management plans

-in the EU companies must submit an RMP to the Agency at the time of application for a marketing authorization -for medicines that do not have an RMP, it is likely that one will be required with any application involving a significant change to marketing authorization -any national competent authority (NCA) in the EU can request an RMP -continually modified and updated throughout the lifetime of a medicine -guideline on GVP module V (risk management systems)

Why assess safety in clinical trials?

-in the late 1950s/early 1960s a tragedy followed the marketing release of thalidomide - resulting in the development f rigorous drug approval requirements -in 1957, thalidomide entered the market in germany as an over the counter remedy for sleeplessness and advertised as safe for everyone including pregnant women, as its developers "could not find a dose high enough t kill a rat" -the clinical trials of thalidomide involved distributing more than two and a half million tablets f thalidomide. Approx 20,000 pts across the nation received thalidomide (including 3,800 women of childbearing age) -by 1960, thalidomide was marketed in 46 coutries. also noted to relieve morning sickness -one year later, OBs began to associate the drug with severe birth defects -at the time, FDA had denied approval as it was felt that the drug application lacked complete and sufficient data on safety and effectiveness -ultimately, this prompted the Kefauver-Harris Drug Amendments Act in 1962 with resultant restrictions surrounding the surveillance and approval process for drugs to be sold in the US requiring that manufacturers prove they are both safe and effective before they are marketed

Future of Pharmacovigilance

-increased safety emphasis -drug withdrawals and risk management -increased regulation -litigation -improved post-marketing surveillance -treatments for chronic -targeting biological mechanisms -global internationalization of regulations

Principal Investigator expectations from monitor

-key for ensuring safety of all patients -reports and updates (maybe investigator brochures, SAE reports, how pt enrollment is going and room for improvement) -ensure that they are current on all these issues -any communications (i.e. telephone, writing, or face to face) must be maintained by PI -responsible for the outcome of the study (ensuring compliance to SOPs, regulations, and oversight for protection of patients)

Metrics for measuring data quality

-key set of metrics (that apply to all trials and projects) agreed upon and documented at the beginning f the stud regarding how the performance of the study will be tracked (if there are any existing standard tracking systems in place, they should be used) -if during a study additional metrics are added to track performance due to an error found in the data, they should be added t the full QC and metric process as well -document the process for collecting, reporting, and communication study-specific metrics into the data management plan

Evaluating risks of drug exposure in pregnancy

-many clinical trials have exclusionary criteria related to pregnancy -typically, little is known about teratogenic potential until data is collected in the post-marketing surveillance period and may take years to identify EVALUATION INCLUDES: -background prevalence of adverse pregnancy outcomes -combined vs. individual rates of birth defects -major vs. minor birth defects -timing of exposure -intensity of exposure -variability of exposure -class effects

Guidelines for checking source documents

-monitor brings forth source documents provided by study staff (+data on CRF) -comparison making sure CRF data is appropriately captured in source document -any discrepancies? what corrections were made? -TRIP REPORT Key areas that monitor is checking in source documents: -compliance across any data points -subject identifier consistency -demographics -medical parameters

Site requirements for Monitor

-monitor looks to make sure case report forms are complete/accurate/logical (data must make sense) (any changes in data points??) -source documentation: look closely at documentation prepared during the time when patient came in for visit (first place with data) - then transcribed onto case report form -needs SPACE to focus on the data and ensure privacy of data (why scheduling visit ahead of time is helpful) -determine personnel availability (if key staff are not available, then visit is not fully maximized)

What rules does monitor follow?

-monitor should follow sponsor's established written SOPs as well as those procedures that are specified by the sponsor for monitoring a specific trial -MONITOR PLAN: what monitor should look at, how often, what is not in compliant or in compliant

Data validation (part II maintenance phase)

-needs to be documentation regarding how the data will be validated -quality control is applied during data validation activities when a specific percent of data is checked for accuracy and completeness -if there are any issues with the data, something called a "query" is written to the site personnel to question or check the data

IND safety letters (SUSARS/ISL)

-notify participating investigators of expedited report in any study of drug (serious, unexpected, related) -within 15 days of manufacturer receipt of report -format MedWatch or CIOMS -investigator is responsible for submitting IND safety letter to their IRB or ethics committee

Source documents that monitor reviews during monitor visit

-physician's office records -physician's appointment book -hospital clinical records for outpatients -drug inventory logs -study coordinator's notes/flowsheets (their organizational tools) -enrollment/screening logs -hospital charts/records -physician notes/orders -anesthesia records -laboratory records -nurse's notes/records -nurse's drug sheets -IV flow sheets -drug dispensing records -physician drug orders (by PI) -pharmacy records -Informed consent! (shows discussion, approval, and understanding by patient about the benefits, risks, and procedures) FIRST THING MONITOR LOOKS FOR when new patient is enrolled, is consent!

Study Coordinator

-prepare paperwork -prepare strategy -ensure overall quality of screening, recrutiemtn, enrollment, participation, maintenance -dispense meds (with pharm) -complete forms -ensure everything followed up -documents/filing

Lack of study adherence evidence

-protocol -drug inventory -source document (is it consistent with data entered onto CRFs?) -incomplete data during monitoring

What may cause protocol deviations/exceptions?

-protocol: lack of precise directions, definitions, info in multiple places (is it actual doable for my site to carry this out? is it clear?) -drug: timing issues (difficult to get it reconstituted/in bag/up to unit in certain time frame) wishing protocol could be more flexible -source document: varying SOPs, misplaced documents, no MR created -communications: unable to find sponsor in timely manner

Aggregate reports in the post-marketing period

-reports requested with defined intervals -help decide whether further investigations are needed/changes should be made -aim is to report all new info from appropriate sources -summarize the medicine's approval status in different countries and any significant variations related to safety -create periodically the opportunitiy for an overall reevaluation of safety -indicate whether changes should be made to an approved medicine's label in order to optimize the use of the product -The EMA requires PSURs every 6 months for 2 years, annually for the following 3 years, and then every 5 years (at the time of renewal of registration)

Preparing for monitor visits

-reviewing prior trip reports and outstanding action items -telephone reports that monitor has seen between other sponsor individuals and the site... maybe lack of understanding? -updated project info that monitor needs to provide site personnel and maybe further discussion with PI SHOULD BE A SCHEDULE: -schedule the next visit at the last monitoring visit (last item discussed) -follow up to confirm with written communication (date/time/what the expectations from monitor is that site should have available)

Concluding monitor visit

-should gather their thoughts and identify the positive points that site has accomplished -share results of the visit with investigator and study coordinator -discuss any issues and ideas for improvement -SCHEDULE NEXT SITE MONITORING VISIT! -providing study staff with case report form completion goals (so staff knows what they need to achieve)

Purpose of monitoring visits

-site adherence to the protocol -case report forms being filled out correctly -site being compliant with all regulations/SOPs -records are up to date (source documentation) -site providing adequate patient enrollment for the study (site identified # of patients at the beginning... should be accurate #) -make sure that pts receiving proper administration/dose of test article (or device is being handled appropriately)

Electronic data capture principles

-the decision to use electronic data capture (EDC) is up to each company, and regulatory agencies are prepared to accept submission for which EDC tools were used -quality EDC systems can be the drivers of the whole clinical trials information management process -plan studies to avoid "last minute" system modifications -develop e-CRFs or data collection tools with teams of individuals from monitoring, data management, statistics, regulatory affairs, and medical -ensure that systems are user-friendly and flexible -ensure that adequate data validation procedures and query management tools are built into the EDC study software

Reporting AEs to regulatory agencies

-the sponsor must report any suspected adverse reaction that is both serous and unexpected -these events are called SUSARS: S-serious U-unexpected SAR-suspected adverse reactions

Quality data inspections/audits

-to ensure compliance with agree-upon data handling, inspections are done to assess the quality of the data -the critical variables identified at the beginning of the study and aligned to the primary and secondary safety and efficacy of the study are usually 100% -audits are also done on sites that may be enrolling a lot of patients r sites that have data that differs from the majority of the sites in the clinical stud -any triggers to identify a site are agreed upon at the beginning of the study and documented

Spontaneous (unsolicited) reporting

-unsolicited reports of AEs, medical device reports, or other required reports, concerning a marketed product -reports received from physicians, patients, pharmacists, others -reported to call center, sales force and other manufacturers -found in literature, identified on web-sites Similar timeframes as clinical trial reporting: -7 calendar days for fatal and life threatening -15 calendar days for other SAEs Same definition for SAE's: -death, life threatening, hospitalization, disability/incapacity, congenital anomaly, important medical event Assumed causality

Summary of MONITOR ROLES at monitoring visit

-verified documentation -discuss and review protocol details with site staff (cleared and clarified any points necessary) -discuss operational issues (how to effectively enroll pts, how to organize site staff...) -discuss investigator obligations (they are accountable for all procedures) -encourage sites to call sponsor at any time with questions True partnership between sponsor and investigative site!

Investigator Responsibilities (questions for monitor visits)

-where do I sign? -how do I determined relationship to investigational product? how do I determine if AEs are caused by product? -can we unblind? -where are all the patients now? (here's who we thought would be successful but ended up being screen failures...) "here's how we looked at things to help prevent screen failures in the future"

Procedures for handling third-party vendor data

1. Establish procedures for collecting, transferring, loading, validating and editing external data through collaboration 2. Identify key contact person for communication and follow through 3. Agreement on procedure - provide written specifications, identify and agree upon critical variables for loading external data into the sponsor's database, maintain a documentation trail, ensure written SOPs are followed 4. Apply quality control - written procedure for safeguarding the blind is critical when primary efficacy data are collected externally, apply quality control procedures to each stage of data handling to ensure reliability

Evolution of drug safety in the US

1906: Food and drugs Act prohibits interstate commerce in misbranded and adulterated foods, drinks, and drugs 1937: Elixir of sulfanilamide containing the poisonous solvent diethylene glycol, kills 107 people 1938: The Federal Food, Drug, and Cosmetic (FDC) Act requiring new drugs to be shown SAFE before marketing (starting a new system of drug regulation) 1951: Durham-humphrey amendment defines the kinds of drugs that cannot be safely used without medical supervision and restricts their sale to prescription by a licensed practitioner 1962: Kefauver-Harris Drug Amendments Thalidomide, is found to have caused birth defects in thousands of babies born in western Europe. This was passed to ensure drug efficacy and greater drug safety. For the first time, drug manufacturers are required to prove to FDA the effectiveness of their products before marketing them 1970: Patient Package Insert - FDA requires oral contraceptives must contain info for the patient about specific risks and benefits 1985: NDA rewrite following deaths and hepatic failure associated with zomepirac and oraflex 15 day reporting defined 1988: Food and drug administration act establishes FDA as an agency of the department of health and human services with a commissioner of food and drugs 1993: MedWatch consolidation of several adverse reaction reporting systems launched 1999: Risk management task force recommends FDA implement a model for risk management 2002: Risk map office f drug safety assumes role in the review and evaluation of risk management plans and the need for post-approval observational studies 2008 FDAAA: The resulting law designed to better inform the public about drug safety and provides new tools for FDA to reduce risks and unsafe drug use 2012: Safety reporting requirements for INDs and BA/BE studies 2013 Drug quality and security act (DQSA) following an outbreak in 2012 of an epidemic of fungal meningitis linked to a compound steroid - outlines several steps for an electronic and interoperable system to identify and trace certain prescription drugs throughout the U.S. (and over 12 final guidance documents in 2015 for medical devices alone)

European commission: device reporting

Adverse Device Effect (ADE): Adverse event related to the use of an investigational medical device Adverse events resulting from insufficiencies or inadequacies in the instructions for use, the deployment, the implantation, the installation, the operation, or any malfunction of the investigational medical device Adverse Event (AE): any untoward medical occurrence, unintended disease or injury or any untoward clinical signs (including an abnormal lab finding) in subjects, users, or other persons whether or not related to the device Serious Adverse Device Effect (SADE): Adverse device effect that has resulted in any of the consequences characteristic of a serious adverse event Same SAE criteria as drugs as well as includes device deficiencies that might have lead to SAE if: -suitable action had not been taken -intervention had not been made or circumstances had been less fortunate -a planned hospitalization for pre-existing condition or a procedure required by the clinical investigation plan, without a serious deterioration in health, is not considered to be a serious AE Unanticipated Serious Adverse Device Effect (USADE): SADE which by its nature, incidence, severity or outcome has not been identified in the risk analysis report Reporting timelines: -sponsor to national competent authority -SAE which indicates imminent risk of death, serious injury, or serious illness and that requires prompt remedial action for other patients/subjects users or other persons or a new finding to it immediately but not later than 2 calendar days after awareness by sponsor of a new reportable event or of new info in relation with an already reported event -any reportable events or a new finding/update to it: immediately, but no later than 7 calendar days following the date of awareness by the sponsor of the new reportable event or of new info in relation with an already reported event -investigator to the sponsor -no later than 3 days after the occurrence of the event

Clinical Data Archiving

After the database is locked, whether paper or electronic methods were used, it must be securely archived (central to the success of clinical trials research) -should begin during the actual clinical trial -the potential for data corruption and version control errors during data storage and transfer is significant and must be minimized to assure consistency of results and data quality -archiving should begin during conduct of a clinical trial, store all original data collected (i.e. CRFs and electronic labs) -access procedures to database servers should be documented, establishing system controls and assigning passwords (especially important in a trial where the original data collection is done electronically and no paper backup exists) -paper documents should be scanned and electronically archived -utilize open formats fr archival, storage, and transport f data (e.g. ASCII, SAS transport, portable document format (pdf), CDISC ODM model) -security of original data sources -database servers as the primary warehouse -disaster handling plan DATA MANAGEMENT DELIVERABLES TO BE ARCHIVED: -database design specs -raw data -audit trail -final data with a standard format -original and/or scanned images of all original documents -procedural variation documentation -database closure (documentation of each database lock and unlock describing the time and conditions surrounding those procedures -additional study specific data management documentation

What is an Adverse Event?

An adverse event is any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug-related -includes consumers, patients, or clinical investigation subjects -also applies t biologics, medical devices, or over the counter products -IMPORTANT NOTE: an "adverse event" need not necessarily have a causal relationship with the treatment or usage An AE may include: -Undesirable medical condition -clinically significant signs and symptoms -abnormal test findings -changes in physical exam findings -hypersensitivity -progression/worsening of underlying disease -lack of effect

Combination Product Definitions

Combination product: product comprised of two or more regulated components that are physically, chemically, or otherwise combined or mixed and produced as a single entity -drug/device -biologic/device -drug/biologic -drug/device/biologic Two or more separate products packaged together in a single package or as a unit and comprised of drug and device and biological products, or biological and drug products A drug, device, or biological product packaged separately that according to its investigational plan or proposed labeling for use only with an approved individually specified drug, device Investigational drug, device, or biological product packaged separately that according to its proposed labeling is for use only with another individually specified investigational drug, device, or biological product where both are required to achieve the intended use, indication or effect

Regulatory Agencies: regulations and guidance documents

Consider the regulatory expectations: US - FDA EU - EMEA Regulations Canada - TPD regulations Israel - regulations of ministry of health China - SFDA regulations South Africa - department of health regulations Australia - TGA regulations New Zealand - NZ joint therapeutic products agency Russia - ministry of health Japan - ministry of health and welfare International conference of harmonization (ICH) World health organization (WHO) and so on... **the number of reports received and entered into FDA AE reporting system (FAERS) from 2004 until 2013 (both have increased)

Data Management Documentation (end of set up phase)

DATA MANAGEMENT PLAN: -complete description of methods to be used to collect, validate, and process data -includes roles and responsibilities involved in the data management deliverable, data flow and timelines -living document updated during the entire life of the study CRF COMPLETION GUIDELINES: -develop guidelines in collaboration with clinical research, programming, and biostatistics from the perspective of the site coordinators and monitors -provide the site staff and the monitors with a correctly completed sample CRF and the CRF completion guidelines at the time of training -stress the importance of not leaving blanks -include a general and page-by-page instructions -include a list of acceptable abbreviations -review data quality periodically, re-educate site personnel, and revise CRF completions guidelines as necessary, particularly for long-term studies -if paper study, ensure the use of permanent media EDIT CHECK SPECIFICATION -programmed checks to ensure accuracy of the data -pre and post entry checks -test data RANGERS AND CONSTANTS: -values agreed upon to be used in edit checks associated with the values provided for the study CODING: (dictionary management) -adverse events, SAEs, medications, medical history, etc -select appropriate dictionaries/version that meet project requirements -implement an audit train for all changes to the coding dictionary -an auto-encoder is useful when coding adverse events and medications utilizing dictionaries with a large number of entries -the coding algorithms should be evaluated, such as its ability to handle synonyms, misspellings, capitalization, word variations, word order, exclusion of irrelevant verbatim text, etc. SAFETY DATA/SAE Reconciliation -safety data is the most challenging and critical of the managment and reporting of clinical trial data -propose practices, procedures, and recommendations for data managers to operate within the project team based on sponsor SOPs -collaborate with statisticians, monitors, and clinical team to ensure that data management practices suport statistical and medical outcomes -develop CRFs with teams of individuals from monitoring, data management, statistics, regulatory affairs, and medical -ensure compliance with regulations -ensure that safety risks are identified and reported accurately LAB RECONCILIATION: -process to ensure lab data is reconciled with data captured in the database -flow diagram/roles and responsibilities -edit checks INVESTIGATOR MEETING PREPARATIONS: -the investigator meeting may provide an early opportunity for the data manager to be in contact with site personnel on a clinical trial -the purpose of a DM presentation is to familiarize the site investigators and their staff with the protocol and CFs, the study procedures, the completion of casebook procedures or schedules, data collection and cleaning processes, and EDC system and equipment if applicable -provide sample CRFs and annotated data clarification forms (DCFs/queries) -prepare a flowchart f the overall data collection process -define team members and site responsibilities for data cleaning

Expedited reporting time frames

DEATH or LIFE THREATENING EVEN: within 7 calendar days of manufacturer received date All other serious unexpected related events: within 15 calendar days of manufacturer received date

Who is involved in data management role?

EVERY SINGLE PERSON involved in a clinical trial

Data validation: listing of typical validation to be completed

Data cleaning or validation is a collection of activities used to assure the validity and accuracy of the data Listing of typical validation that needs to be completed to ensure the validity and accuracy of the data: -raw data accurately entered into a computer-reliable file -character variable contain only valid values -numeric values are within predetermined ranges -eliminating duplicate data entries -checking if there are missing values -checking for invalid date values -checking fr uniqueness of certain values, such as subject IDs -checking for invalid date values -verifying that complex multi-file rules have been followed (adverse event leads concomitant medications or procedures)

Task flow in data management

Database is evidence for efficacy and safety assessment 1. CRF Design 2. Database Design 3. Data Aquisition 4. Data Verification 5. Data Consolidation 6. Database Closure

Part III Database Closure - database lock

Database lock: -procedure defining database closure method -document completion of all defined tasks or criteria prior to database closure -ensure that all team members are notified and edit access is removed and documented at final database closure -have written procedures with clear criterion for unlocking a database after closure Post-database lock activities: (several activities completed that still have data management involvement) -the clinical study report aka CSR -any publications or submissions -new drug applications -label changes to a study drug, including data that was reported in the clinical database

Causality assessment

Did the drug cause the event? Reasonable possibility that the event was caused by study drug? Consider: drug exposure, time of event to exposure, known drug profile or class effect, de-challenge, re-challenge, labs

Drug safety monitoring boards and endpoint adjudication committees

Drug safety monitoring boards: -committee of diverse members of experts in statistics, therapeutic/disease, and data management (not employees of sponsor or CRO) -review aggregate unblinded data -role is to independently monitor the patient safety -may recommend early stop of study as a result of findings -not all studies have DSMB

Evolution of risk management

Early risk management programs that preceded "RiskMAPs" and "REMS" -clozapine - "no blood, no drug" program implemented in 1990 Developed to prevent agranulocytosis Thalidomide - system for thalidomide education and prescribing safety (S.T.E.P.S.) program -implemented in 1998 -developed to prevent fetal exposure -managing the risks from the medical product use (published May 1999) -report to the FDA commissioner from the Task Force on Risk Management asked to examine the current system used to manage risks associated with using medical products -FDA Risk Management Guidance Documents (finalized March 2005): goal was to produce guidance for industry on risk management activities for drug and biological products

Development Safety Update Report (DSUR)

European Medicines Agency (EMA) -a common standard for annual clinical trial safety reporting -promotes consistency and efficiency from region to region 4 components: 1. summarize the current understanding and management of identified and potential risks 2. describe new safety issues that could have an impact on the protection of clinical trial subjects 3. examine whether the information obtained by the sponsor in the reporting period is in accord with previous knowledge of the product's safety 4. provide an update on the status of the clinical investigation program

Combination Product Adverse Event Reporting

FDA: -office of combination products has published a concept paper about AE reporting for combination products and intends to publish regulation to clarify AE reporting requirements EMA: -update on DSUR -If the DSUR is for an investigational drug that is also under development as a component of a fixed combination or a multi-drug regimen summarize important safety findings -regulations recommend strategies for preparation of DSURs

What goes into a SAE report - MedWatch form

Form FDA 3500A patient info adverse event/product problem suspect product(s) suspect medical device(s)

Contributions to product development

From the moment a compound is identified in early drug development, data is collected to better understand its potential in helping patients. As the compound moves past pre-clinical trials and into man in phase I, II, and III trials, more data is collected and statistical analysis is performed for decision to be made concerning the future of the drug and if it has potential to be submitted to the regulatory authorities for final approval as prescription medicine

What goes into a SAE report cont.

I. reaction information II. suspect drug(s) info III. concomitant drug(s) and history IV. manufacturer info

Aggregate reports to regulatory agencies

IND Annual report: -within 60 days of the anniversary date that the IND went into effect a summary report is submitted to the regulatory authorities -summary of SAE's by body system (MedDRA), frequency and severity -summary of IND safety reports submitted in the last year -deaths (listing cause of death for each) -discontinued due to AE -description of info pertinent to understanding the drug (dose response, bioavailability, etc) -summary of any significant manufacturing or microbiological changes made during the past year

CRF quality check

In addition to a QC of the data, there is also a QC done to ensure that the CRFs match the variable and fields in the clinical database. If there are any issues or fields on the CRF that have not been captured in the clinical database, it should be addressed prior to database lock -inspect CRF-to-database early, process control, a standardized and validated data collection process -analyze anomalies discovered during the data handling process, and take corrective action -perform and evaluate a data quality impact analysis and propose system and process changes

Causality

In clinical trials, the investigator and the sponsor provide an assessment of causality -grading scales may vary: from many selections to two selections -possibly related - known profile of drug or class, reasonable temporal sequence, dechallenge-rechallenge, not result of disease process, no other agents in use -unrelated - not in known profile f drug, could more likely be explained by alternate factors, e.g. underlying illness, other therapies -may determine if blind is to be broken

Interim data review (part II maintenance phase)

Interim review: Overall check of what has been entered for the patients mid-way through the study **agreed upon at the beginning of the study and documented int he data management plan types of interim reviews include: (study milestones) -a mid-study or interim database lock -safety committee review -FDA requests (review of data from regulatory authorities) -data management timeline (project plan)

Monitoring Procedures

Many sites will not have established written SOPs for the monitoring visit so - especially if the coordinator is new to research, expectations for visit should be VERY CLEAR and written if at all possible in advance

Regular site visit activities

Monitor has a list of things they go through (same as the one site receives) -check enrollment -check CRFs (adherence to protocol, no missed AEs, accountability of drugs) -files (complete regulatory binders) -facilities (ensure compliance... ex: lock on cabinet door) Follow up!

Part 1 Set Up Phase

Protocol: clinical team reviews to ensure understanding of data for collection/how to collect it

Elements of REMS

REMS must include Section (d) elements: -"minimal strategy" Timetable for submission of assessments of the REMS strategy: -18 months after approval -3 years after approval -7 years after approval Frequency may be increased or reduced as necessary; may be eliminated after third year if FDA determines that risks have been adequately addressed Section (e) Elements: "Additional Potential Elements of Strategy" -(2A) Medication Guide -(2B) Patient Package Insert -(3) communication plan to HCPs Section (f) Elements: "Elements to assure safe use" -(A) requirements to train/educate prescribers -(B) certification of pharmacies, practitioners or healthcare facilities -(C) restrictions on distribution sites -(D) Mandatory laboratory tests -(E,F) other required monitoring or registry

4 key areas that monitor covers during monitor visit

Remotely review some of the date thru case report forms prior to going to the site 1. Documents for study 2. Drugs (investigational product and how its being dispensed) 3. Supplies (might be falling short?) 4. Monitoring requirements including SOPs that must be discussed face to face with the investigator **if calendar does not permit monitor and PI to meet face to face... responsibility of monitor to follow up with PI via phone to explain findings

FDA Device reporting

Reportable occurrences including: -device failure -malfuntion -improper or inadequate design -manufacturer concerns -labeling concerns -user error Reporting deadlines: -30 days after manufacturer awareness -5 days when an AE necessitates remedial action to prevent an unreasonable risk of substantial harm to public health or if FDA requests **Use form FDA 3500A submit annual report including: -manufacturing changes -design changes -labeling changes -unpublished reports from studies -reports from scientific literature post-approval reports on safety, efficacy and reliability

Safety reporting

SOLICITED REPORTS are those derived from organized data collection systems, which include clinical studies, registries, surveys of pts or healthcare providers, or information-gathering on efficacy or patient compliance SPONTANEOUS REPORTS are unsolicited reports of AEs, medical advice reports, or other required reports, concerning a marketed product

Seriousness vs Severity

Severity: measure of intensity rating scale (mild, moderate, severe) based on patient/physician evaluation (just because an AE may have a rating of "severe" it does not necessarily make it serious) Seriousness: NOT the "clinical" definition of seriousness. REGULATORY definition based on defined outcomes: -death -life threatening -hospitalization (new or prolonged) -disability/incapacity -congenital anomaly -important medical event

Monitor's key role

Site adhering to study!

Data Privacy

The standards surrounding the protection of personal data -Building and maintaining a platform to maintain a high degree of privacy protection (or security) for research subjects during the data collection and management procedures -All applicable regulations should be considered to ensure full compliance with government regulations **standards are different across the world -Educate and train all personnel on data privacy concepts, include company policy, regulatory agency policy and applicable state, federal, and international law -Design data collection instruments with the minimum subject identifiers -Enforce a policy of "NO" access to personal data as a baseline. Make compliance with data privacy regulations a central focus of audits and a contract contingency when using external service providers -Maintain proper physical and electronic security measures (passwords that only trained users can access) -It is beneficial to create a case report form module that contains a question ensuring the subject has read, understood, and signed the informed consent -All documentation regarding a patient should have the same enrollment codes or identifiers associated with them and there should be no personal information (ex: name) on ANY data submitted to the trial -Same privacy procedures should be followed for genetic data that's collected (and blood/lab samples)

Database Set-Up and Validation

Two areas of validation: 1. validation of clinical database 2. Validation of programming related to the development of a study or protocol-specific database Validate, Test, Define -Validate database in their local environment -Test the set-up and programming of each study to assure that any new code generated or new system functionality used for the study works according to the user's specifications -Define the testing methodology, scope, problem reporting ad resolution, test data and acceptance criterion within the test plan Understanding the Program -Identify all intended uses of study-specific programming -Use organization standards to document programs -Make use of code libraries Test for Accuracy -Primary concern is the dependability of the clinical database -All tests are designed to conform to established requirements for completeness, accuracy, reliability, and consistent intended performance -Additional validation: data entry screen, batch data transfer to the clinical trial database from separate data entry systems AFTER FULL VALIDATION -Validation must focus instead on specific study or protocol database design and implementation -Validation can be addressed in three major categories: 1. Database design 2. Data entry or capture 3. Other study-specific programming Database Specifications: -Database design should be based on standard data architectures within a sponsor organization -Database specifications should at a minimum provide the following for every variable: name and label, data set label, panel, or other logical group in which the data belongs, type (numeric, character, integer, decimal, date), length (including number of characters before and after the decimal point where applicable), definitions for all coded values, indication of the origin of the data, algorithms for derived or calculated variables Testing Transfers -database entry or capture validation -duplicate records and discrepancies between first and second pass data entry -data loading or transfer programming -best practices include identifying all intended uses of study-specific programming and testing each logic condition in the programming based on a test plan (there is a first and second pass validation to ensure that any errors found during the UAT are corrected)

Data for E-CRF

When a trial is running and data is collected electronically, it flows to and from different systems for collection and analysis purposes. Several different systems feed electronically into one database. There are occasions where data would flow from the clinical database to other systems... this could be for study-related processes or safety-review processes as documented in the clinical study protocol

Why does the industry need data management?

Will prove/disprove safety and efficacy of drug

Reconciliation

comparison of the safety database to the clinical database -all AEs are reported on the CRF and entered into the clinical database -all SAEs are reported to the safety department and entered into the safety database -periodically must ensure data consistency -always reconcile prior to database lock prior to report generation

Investigator Brochure

completed at the compound level includes a wealth of information but for the purposes of this presentation it includes safety information on the compound used as reference for the investigator used as the reference for "expectedness" assessment

Referential Questions

ex: "Did the subject have open heart surgery? If no, skip to the next page" -questions that reference more than one form -for example: the adverse event form usually has a follow up question regarding any relevant medications that were taken as a result of the event (both the Adverse Event and Concomitant Medications forms will need to be reconciled with all data and related timings of event and medications) -there are often discrepancies with data captured across forms, so whenever possible it is best to limit questions that refer to another CRF _**Can lead to problems during revision BEST PRACTICES require that, when possible, no question refers to another question contained in a remote section of the CRF

Protocol

key document crucial to success of clinical trial! shared with regulatory authorities, site personnel, sponsor, potential consultants... posted for transparency on governmental website (clinicaltrials.gov) road map to what the site must follow to ensure patient protection and adequate oversight Sections to protocol: -inclusion/exclusion: outlines for PI those patients that qualify and those that don't -laboratory collection procedures (understanding of what labs/when/what volume)... looked at by IRB -adverse experience/safety area (usually most in depth)- contains description of AE and identifies how the process should be carried out if AE occurs -Withdrawal (why would staff withdrawal a patient?) -Analysis (with all statistical reasoning) -Evaluation (several points- used to determined if product is efficacious) -Screening procedure (may be short or long-may be asked to be removed from certain medications-key to know!) -Flowchart (the "cliff notes" of everything that has to be done during the patient journey in a clinical trial... i.e. when should labs be drawn? drugs be administered? -Assignment (today dosing regimens are electronically assigned) -Medication or device under investigation (if medication, what is the dosing regimen? how will pts be randomized?) Never leave "home" without it!

How is data managed?

managed in several different ways depending on an individual's role

Case Report Forms - CRF Process

steps for designing/implementing a CRF: step 1: design CRF to collect data specified by the protocol step 2: document the process for CRF design, development, approval and version control (modifications) step 3: make CRF available at the clinical site prior to enrollment of a subject (so they are clear how to document data) step 4: document training of clinical site personnel on the protocol, CRF completion instructions and data submittal procedures prior to enrollment of a subject -Keep questions, prompts, and instructions CLEAR AND CONCISE -Design the CRF to follow the data flow from the perspective of the person completing it -Minimize referential and redundant data points within the CRF whenever possible. Keep data independent. -Establish and maintain a library of standard forms (so you don't have to re-create new forms for every study) -Always phrase questions in the POSITIVE -Data should be collected in coded form (i.e. use check boxes when ever possible) -Maintain consistency in the order of similar choices throughout the CRF -Use consistent formatting and consider the intended use of the tool -Provide form completion instruction and definitions for times not directly measurable -Questions should be specific and clear enough to assure complete and comparable data are obtained across various populations

Study Coordinator responsibilities

the other individual at the site who is integral to ensure that tactical aspects of the study are being done correctly -prepare for the study (i.e. develop forms, track info, decide how to perform screening procedures) -strategy for how they will make contact and recruiting patients (media, apps, tv, newspaper... maybe already have database) -recognize recruitment barriers -organize enrollment procedures/patient visits -make sure pts sign consent and understands what is happening/their responsibilities -give opportunity for patients to ask questions -maintain inventory of investigational products -maintain patient compliance -collect/input data to case report forms -continuous communications with ethics review board Make sure study/data is HIGH QUALITY Daunting task to organize all this! Key for study coordinator to figure out best strategy for all the steps (any issues? bring in PI immediately)

Pharmacovigilance

the world health org (WHO) defines pharmacovigilance as the science and activities relating to detection, assessment, understanding and prevention of adverse effects or any other drug-related problem AKA: drug safety, product safety, safety reporting

Purpose of Monitoring Visit from site perspective

thoughts: -Monitor helps you organize, gives you tips and provides you with helpful aides -they come too often/too infrequently -SOPs vary between sponsors and CROs actual purpose: -understanding of the protocol - eligibility requirements, unstated parameters, reporting standards -correct completions of case report forms: definitions, source document issues -compliance with regulations and THIS sponsor SOPs - every sponsor and CRO is different -be certain necessary records are available -ensure adequate patient enrollment, discuss challenges, display screening efforts, ask about other sites that are being successful (look for tips) -ensure administration and deposition of the test article was correctly done (remove extras)

Minimum Information for safety reporting

to have a safety report you must have: -identifiable patient(s) -suspect product(s) - a drug, biologic, medical device, or OTC product -AE -identifiable reporting source

Frequency of adverse drug reactions

very common, >10%, dizziness, fatigue, tiredness, difficulty in concentration common, 1-10%, sedation, memory problems, depression uncommon, 0.1-1%, ataxia, somnolence, skin rash rare, 0.01-0.1%, Stevens Johnson syndrome, nephrolithiasis (topiramate) very rare, <0.01%, aplastic anemia (phenytoin), glaucoma (topiramate)