Module 3

Marketing strategy: what is it?

"sound strategy starts with having the right goal" -what do you want to achieve? -what are your goals? "the aim of marketing is to know and understand the customer so well the product or service fits him and sells itself" -peter drucker -understand the consumer! (where research is crucial) -ask the right questions -understand the target market "marketing takes a day to learn. unfortunately it takes a lifetime to master" -philip kotler Marketing strategy: the process of creating, communicating, and capturing value by building and maintaining long term relationships with customers -where are we today as a company, where do we want to go, and how do we get there? -create a comprehensive plan

ICH Guidance

(focusing mostly on US guidelines... but one ICH guideline comparable to US code of federal regulations, but more specific sometimes) ICH E6 consolidated guidance - good clinical practice (Guidance for Industry) -very compatible with US code of regulations -a little more specific, like 5.19.3 auditing procedures

type of regulatory audits: GCP

(predominately focusing on US code of regulations eCFR) look at the entire clinical study design and safety and efficacy of product and patient

Review best practice: how to perform inspectional review

-accuracy and completeness -language and grammar -tables and figures (clarity, purpose format) -abbreviations -references -cross-referencing (both within and across documents) much easier than strategic review, but also much less helpful (anyone can do this)

Other necessary notifications

-ancillary personnel, such as lab and pharm technicians, nursing staff, other physicians, and consultants may want to be notified -newsletters and research publications keep staff informed of research -at beginning, agree upon rules for publications! what process does PI need to go through to follow all requirements requested by sponsor?? -administrators are looking at credibility for the institutions and are interested in areas for improving clinical research in the future -corporate communication (not only for internal, but for spread to community) - shows community what they're contributing to, helps sponsor for the future

type of regulatory audits: GLP

-animal studies or specific aspects of non-clinical lab operations common documents used in GLP audits -SOP indexes -QA audits -floorplans -list of CROs -freezer inventory -protocols and amendments -organizational charts -raw lab data -pathology data -computer systems (design, input/output data) regulations we might use: -21 CFR 58.90 (Discusses animal care/housing) -21 CFR 58.105 (test and control article characterization)

Developing a marketing plan

-blueprint or road map -base your plan on marketing research -remember your target market and how your product relates to it -don't forget your competition (and your unique value proposition in relation to them) -create a mission statement (so all goals are aligned - a way to define company... brief, what company does, who is key market, unique proposition? -finalize your promotional strategy and budget (how you plan to communicate with target markets) -set marketing goals (and plans to monitor results)... set a timeline!

Positioning example: pharma

-build emotional connection with customers (almost as important as functional characteristics in terms of trust, and ultimately this influences preferences for what doctors prescribe and recommend) -highly influenced by marketers, and they're crucial to decision making (why they show happy people playing in the field instead of talking about how specifically drug works)

Understand your competition

-competitors come in many shapes and sizes (ex: homeopathic meds... or taking extra vitamins instead of changing meds...) -who are my competitors and what are they doing? -what other options do customers have? (craigslist instead of retail stores...) -how are other products different from mine? -what are their strengths and weaknesses? -how are they meeting customers' demands? -what can I do better to meet customers' demands? (ITS FROM CONSUMER PERSPECTIVE)

Consumer differences

-consumers are different in their needs and preferences -many variables impact how consumers respond to a marketing mix -the same product targeting to different audiences may have a different message

Marketing a product

-developing marketing strategy -understanding your environment -understanding your competition and customers -segmenting, targeting, and positioning -SWOT analysis (what does your company do well/poorly?) -developing marketing plan -ethical issues relevant to marketing strategies

Interview prep

-do your homework -know your audience, any specialties, therapeutic areas, position description -maybe phone or webcast interview or in house -know the difference between being friendly but not friends (don't be chatty or overshare) -don't complain about a prior employer -stay positive -use common sense -keep an eye on non verbals -try to assess culture pre-interview -what you say and how you say it is a reflection of who you are

Search for the right place

-do your research -get feel for different environments -do I want to be part of CROs or more of a corporate america/pharma type? -training programs... what is offered/needed? -always SOPs associated with different companies... so no matter what we will have ongoing training process throughout career -what agencies have good reputations, treat staff well, and have the same philosophies that I have

final tips

-don't burn any bridges! -fulfill all your obligations - don't be a hopper -make a lasting impression -remember who you are representing -communicate concerns -give proper notice - vacations/days off -remember what you've done and learned (good or bad) and apply it to next job

why do we audit?

-ensure accuracy and effectiveness -safe, effective quality products created and maintained -conducting ourselves in compliance and conformance with regulations -decrease inspection observations

Documents medical communications professionals use

-every document in the clinical communications continuum (CCC) -publications -presentations CCC: the continual stream of documents that leads from the initial idea to the final submission to regulatory authorities, approval (hopefully), and to the market

Get and keep connected

-foster a huge network of colleagues -join industry orgs and attend conferences -groups like ACRP, DIA, SoCRA -read publications (the Monitor... now clinical researcher, therapeutic innovation...) -utilize technology (facebook and linkedin) -job boards -enlist agencies (either we seek out or they seek us out)... keep in mind you want to remember who you spoke with, if they discussed a position make sure you note actual title, make sure they are reputable... take notes, get detailed info -submit resume with full disclosure ... don't "dual submit" -be honest about needs/wants in a positions, limitations... -be prepared to be flexible/negotiable -permission to submit MUST be given

Guidance and Regulation Documentation

-impossible to memorize all key guidances and documentations... just know where to go to obtain them! (links at end of presentation)

Role of auditee

-inform all personnel being audited -assign representative to be liaison between auditor and department being audited -provide access to documentation for the auditor -assist in clarifying any issues that may arise

Regulations and Guidelines

-key to auditing, know criteria! -don't have to have them memorized, just have them handy -know the regulations and guidelines! and company policies and SOPs (to make sure key deliverables of the standard are being met)

Auditing components

-know criteria we're auditing against -know the appropriate regulations, guidance documentation, company SOPs -much easier to obtain with technology

Understand your marketing environment

-marketing activities do not take place in a vacuum (what's going on in world around you? what are people needing) -competitive, economical, political, legal, regulatory, technological, and socio cultural forces affect the marketing mix Marketing mix and four Ps of marketing: 1. Product/service being offered 2. Place (where to buy it) 3. price they would pay 4. promotion or any type of communication with consumer Food and bev industry: -one example is the negative publicity around health effects of soda -some companies have introduced new products or made them healthier -concept of menu labeling includes consumer purchase decisions (ex: calories listed) -consumers in restaurants with calories listed purchased fewer calories -people more likely to say yes their decisions were swayed by calorie intake Understanding marketing environment cont: -a good portion of what's relevant about your marketing environment depends on your industry (what regulations/technology exists...)

Medical Communications

-overview of the drug development process -describe the role of medical communications in the process -understand how current position fits into big picture

Site obligation at study end

-prior to monitor coming, coordinator needs to set up final visits for all the patients -do letters in advance if study is ending early and acknowledge patients for their contribution -ensure smooth transition to routine medical care and treatment if needed (coordinator has discussion with pt to see if any info obtained from pt during study, if pt wishes for it to go to PCP...) -send completion information and any therapy modification to the pertinent medical team -patient may develop relationship with site... define ongoing communication allowances with completed patients (has to be discussed with pt at final visit and policy established with site personnel) -ensure storage nearby for at least 6-12 months after last query (doesn't include the archiving that could go on for several years... this is more of a nearby place where if there is some question that comes up soon after close, instead of going to remote vendor, this data would be easily retrievable) -after 12 month period (differs according to institution) ensure remote storage for duration of time specified by contract (specify how long through contract) -keep log of patients contact for results and unblinding (coordinator needs to figure out how to maintain log, what studies they're in, contact info...) -determine whether to return, recycle or toss extra supplies Ethics committee is for the PROTECTION OF PT SUBJECTS (objective, no tie in directly... need to better understand how trial was conducted/how pts were handled/if policies were followed) -summary report! -notify ethics committee that study is closed and submit the final continuing review -notify grants and budget department (help the site put forth appropriate budget so sponsor may respond favorably or not to it) -at end of study, provide final numbers for pts screened, enrolled, completed, drop-outs, dates of all visits, and notice of any special billing, invoices, and payments

Roles of the auditor

-review policies, plans, procedures, practices -review previous audits

Resume Prep

-sell yourself! provide a skill set summary (here's why you should hire me): -be thorough and detailed but not too wordy -make info easy to read and highlight areas you want employer to acknowledge -bullets -bolding company names and job titles -include start and end months for positions -keep job descriptions below actual job -therapeutic experience - table with details -sell longevity and promotions -education, licensures, certifications, training's, awards, special skills -how to handle job changes/gaps: how will you best explain this withough causing red flag

Site close-out: sponsor

-should have contacted site and identified site expectations for site close out -monitor confirms there are signed informed consents for all study subjects (any updates to the informed consent d/t amendments - pts signed all versions) -monitor makes sure there is documentation in the source that the patient did see the IC, given a copy to take with them, and given ample time to ask questions from PI -ethics review board notified of site closing out (many IRBs/ECs have different requirements) - has there been any safety issues? AEs? patients compliant? any violations to compliance from study staff viewpoint? -monitor looks for a copy of ethics review board notification and study summary (different ECs handle this differently), it could be placed in close out site report that this is still outstanding... monitor will follow up to retrieve/submit it to trial master file -monitor goes through the study files at the site COMPLETELY (all regulatory docs, correspondents, AEs, items submitted to EC, ICs, 1572s, signed protocols, amendments...) -drug inventory and reconciliation is completed for return to the sponsor If monitor finds gabs or omissions, it is best to see if these things can be resolved while monitor is still onsite (closing the loop) monitor has gone through all the files, looked at the drug, reviewed patient charts for last minute questions (perhaps from queries), checked ICs, now ready to wrap up responsibilities! what to share with site: -instructions for return of clinical supplies (lab tubes, needles, equipment) -let staff know if supplies can be retained at the site or returned to the sponsor or vendor (make sure no conflict of interest or coercion! some sites not allowed to retain any supplies) -retention of case report forms (electronically), study file, and source document -materials need to retain together (if being retained) -any other monitoring tasks required

Ethics and marketing a product

-should it be up to the consumer to make the decision about what medication is most appropriate for them, or should it purely be left up to the doctor? -FDA has an office called "office of prescription drug promotion (OPDP) -reviews script drug advertising and promotional labeling to ensure info contained is not false or misleading -review complaints about alleged promotional violations -initiate enforcement actions on promotional materials that are false or misleading -are they doing enough? -are they able to protect the consumer and allow the consumer to make informed choices? -should it be up to the consumer about which products are best for them? **some of the most effective strategies may also be the most controversial**

Understand your environemnt

-threats can come from competition as well as FDA regulations... (Ex: FDA to revisit its policies on regulating homeopathic meds) -you must understand what is going on around you to be effective at developing and executing a marketing plan for your product

Positioning

-what is your value proposition? what makes you unique and better than your competitors? -Ex: southwest changing their positioning strategy now that more airlines allow free bags... -for pharma products, goal is to still have a unique value proposition - efficacy, dosing, tolerability, safety -you can position your product on common attributes, as long as you are the first to promote them -over time, if a product is not diff. from competition, it may end up losing market share

Thing about your consumers

-who are they? -who buys? -why do they buy? -how do they buy? -where do they buy? -when do they buy? -how do consumers learn info about a product? these all impact decisions consumers might make!

Communications Continuum

-who had the first idea for...? (any drug) -where did that idea come from? -it came from cooperative effort between professionals all across pharma industry -in the past, scientists developed drug, tested, found it was effective/safe, THEN thought "is there a market for this?" -this has changed today drastically -professionals come together early and talk about what kinds of drugs could make a difference in the market place -TARGET DRUG PROFILE is developed! by the end of development process, profile emerges that says "drug in this class that treats this and can make the following claims is something we can sell" TARGET CLAIMS developed -ex: the drug is more efficacious, or similar to something else but safer, works faster or longer, or can produce it quicker for less money DEVELOPMENT PLAN: -how are we going to develop this specifically? -a lot of work and thought goes into this -seeks to answer the questions: what do we need to show? what data do we need to generate to make the claims that we want in target drug profile? -developers and researches develop all the questions they need to ask, data they need to get... -answers to those things all come together in the overall development plan PROTOCOL: -developed for individual studies called for -phase I (looking for healthy volunteer studies except oncology), defining safe dosage -phase II: actively testing safety of the drug in various populations (ages, genders, sub populations with conditions) -phase III: large and complex trials with as many patients they can get, safety and efficacy of drug tested -protocol for each study is the instruction manual: what kind of patients, what to screen them for, what to look for in study, what data are we collecting, how will we analyze CSR -as studies complete, go from protocol phase to reporting and analysis phase of study -CLINICAL STUDY REPORT produced during this stage -reports on all data generated in study, patient info gathered during study, and anything that might have happened (expected or unexpected) -CSR kind of answer sheet to the protocols (protocols ask the questions and give directions), study report gives the answers SUBMISSION -once all studies called for have been run, pulled together into submission -to the FDA (USA) -EMA (europe) -Health canada -regulatory authority anywhere in the world -asking for permission to market the product in their country LABEL (arrows from target drug profile and submission) -end product of entire clinical development process -top document in communications continuum -first thing you see when you pick up a script (folded piece of paper) -every document along the way depends on the document before -target drug profile leads into label because we need to judge ourselves against that profile... we said at beginning that said drug would be marketable... before we get drug on market, assess how well we delivered target drug profile (did we make claims we said we wanted to make?) Medical communications professionals work on every document in communications continuum (someone involved at every step) -not just writers... they are true specialists who are broadly focused across multiple functional groups at each step along the way

Audit

1. A formal examination of an organization's or individual's accounts or financial situation, b: the final report of an audit 2. a methodical examination and review MORE ACCURATE FOR US: a systematic and independent examination of trial-related activities and documents to determine whether the evaluated trial-related activities were conducted and the data were recorded, analyzed, and accurately reported according to the protocol, sponsor's SOPs, GCP, and the applicable regulatory requirement

Auditing techniques

1. Audit team selection -look at audit "team" -includes a lead auditor (usually the most experienced) -effective use of resources, review education and expertise of a team, have a cross-functional team! 2. audit team preparation -audit plan, purpose, and scope -plan may begin a year prior, map out audits (plan for each one), road map/guidance for each audit 3. Hierarchy of auditing standards -criteria that you're auditing against -look for global regulations and guidelines -local (country specific) regulations and guidelines -sponsor policies, practices and procedures -contracts and specifications 4. Establish requirements against which to audit -includes: standards, contracts, specifications, policies, guidelines, etc -determine from each, what are the deliverables we will look at during audit after determining deliverables... 5. Document! -importance and utility of quality documentation -track and record: what was reviewed, what was seen, who was interviewed, observations made, etc. -ex: maintain excel spreadsheet, saving forms/highlighting, possibly doing screen shots 6. Use of checklists, guidelines, and log sheets -helps keep audit focused -assures observations are sound and make sense with criteria utilized -provides method of back tracking data and documents (ability to recreate the data) 7. Development of data collection methods -important to ensure that multiple auditors are operating on the same page! -determine strategy for reviewing and collecting info 8. Audit plan communication and distribution -important anytime, but especially when auditing externally (vendors, investigators, etc) -requires preparation, coordination, scheduling flexibility (make sure everyone will be available for the actual audit) 9. Audit performance -starts with opening meeting -audit team management and communication (throughout whole thing) -audit implementation (documentation and requesting additional documentation, conducting interviews) -audit analysis (non compliance??) -wrap up meeting (daily meeting) and a wrap up meeting at the end of the audit 10. Audit reporting (after audit has been conducted) -audit reporting: distribution of audit report, prioritizing, significant observations, conclusions -follow ups: corrective preventative action (CAPA) and closure... prevent reoccurence!! -once CAPA completed, then audit report can be CLOSED

Market Segmentation, Target Marketing, Positioning

1. Market segmentation: dividing a market into meaningful smaller markets or sub-markets based on common characteristics (dividing market into select groups of people... don't have to create things for all!) 2. Target Marketing: evaluating the market segments, then making decisions about which among them is most worthy of investment for development 3. Positioning: communicating one or more sources of value to customers in ways that connect needs and wants to what the product has to offer. Positioning strategies are executed through the development of unique combos of the marketing mix variables

Types of audits

1. Vendor audits -sponsor working with vendor, ensure oversight 2. site audit -investigator site, lab, etc 3. Preapproval audit -ensure that all areas of New Drug Application are acceptable before its approved 4. Due Diligence audit -sponsor lookingat a joint venture with another company (ensure its a good fit) 5. System/process audit -looking at SOPs or processes 6. Routine/follow up audit -follow-up to previous audit to ensure CAPAs were conducted and everything is acceptable now 7. For Cause audit -addresses specific issues or concerns that have come up that you might be asked to audit because clinical team has concern about site, etc...

how are audit results measured?

1. objective evidence -observed or documented evidence that is uninfluenced by prejudice, emotion, or bias (ex: looking for inclusion/exclusion, BP results, checklist for ICFs, quality of life questionnaires) 2. qualitative methods -qualitative data collected through interviews, open ended questions, discussions, etc. (ex: interview a colleague to learn their process, have someone demonstrate something and you watch) 3. quantitative methods -used to collect quantitative data like sampling and taking measurements, etc. -cannot always look at 100% review...take samplings of documentation to review (i.e. 10%) -formulation (i.e. square root +1 to determine how many sites get audited) -usually use a combination of these techniques

Critical questions

1. who am I? what is my personality? do I like to be among people or am I very independent/able to work from home? 2. restrictions to travel? 3. employment history and background... what did I excel at? what do I need development on? 4. where do I want to go in my career? 5. Do I want to be corporate or independent? Self analysis to determine what area I want to put my foot into

IRB

An independent entity made up of medical, scientific, and nonscientific members whose responsibility is to guarantee protection of the rights, safety, and well-being of the human being involved in a study through, among other things, continuous review and approval of the study protocol and amendments and the document of the informed consent of the subjects of the study.

Options for employment

Direct hire: -salaried employee of a company -benefits package Contractor position: 1. W-2 (taxes withheld, benefits offered sometimes, direct deposit option) 2. 1099 (no benefits, considered an independent instead of incorporated, expenses for incorporation, obtaining insurance, office supplies... tax deductible), have to show proof/documentation of insurance policy

Positioning example (dove)

Doves communication strategy: they want women to accept themselves as they are and think of themselves as beautiful -signs on two doors: beautiful and average -most women chose "average" door

Auditing references

FDA main site FDA: CFR EMA main site EMA document library ICH PAHO PHarmWeb.net

SWOT analysis example: pharmaceutical

Goal: uncover opportunities, think of potential threats, and think of best way to utilize strengths and fix weaknesses Strengths - internal: -cost effective tech -advanced clinical trials -top notch process development labs (market dominance may be helpful... big name, more money...) Weaknesses - internal: -minimal funding for R&D -patents expiring -controversies regarding drug safety Opportunities - external -changes in tech -global penetration -increasing awareness about healthcare needs Threats - external: -regulatory changes -economic slow downs -international competition (changes to insurances, reliance on transport from other countries...) Prioritizing factors with use of SWOT

GXP

Good clinical, manufacturing, labratory, pharmacovigilance practices

type of regulatory audits: GMP

Good manufacturing practices -product manufacturing (site, environment, room...) -guidance for industry -Q10 pharmacy -ISO 9000 _ICH Q10 procurement of: -materials -facilities -utilities -equipment production of product: -packaging and labeling -QC and QA -sample retention -release, storage, and distribution basically checking to ensure quality of: -policies -procedures -specifications check areas for: -cross-contamination -ability to clean -flow -temperature -space -free of vermin

Auditing comparison

ICH Guidelines: -specifically provide guidance that sponsors perform clinical quality assurance audits CFR: -no specific regulation requiring sponsors to perform clinical quality assurance audits FDA officials do note that quality assurance auditing has always been a cornerstone of sponsor's success in GCP - lack of explicit regulatory requirements has been a silent topic over the years

IEC

Independent organization made up of medical/scientific professionals and nonscientific/non-medical members, whose responsibility is to guarantee protection of the rights, safety, and well being of the human beings involved in a study and to provide a public guarantee of the protection, through, among other means, the review and approval/favorable opinion of the study protocol, the capability of the investigator, and the adequacy of the installation, methods, and materials that will be used upon obtaining documenting the informed consent **basically, IRB and IEC perform same roles, just called differently depending on continent IRB = US IEC = ex US

Prescription medication example

Lipitor -reduces cholesterol -had a clear strategy... used to be one of its kind -once patent expired competition came (generics and other cholesterol reducing drugs) -target market: end consumer and doctors (realized cost could be an issue) -now changed pricing strategy (current marketing mix says price is a big aspect) -market growth: need to understand the international market -environment: are people having high cholesterol at a younger age?

A successful career in clinical research: the industry from a staffing perspective

Mergers and acquisitions: a lot in the industry going on... when this occurs, many people have opportunities to be looking at new positions Pipelines: strong pipelines in interesting therapeutic areas (providing you a challenging opportunity for career growth) Outsourcing: significant outsourcing of trials from pharma/biotechs to CROs Mid level: high demand for mid level positions - primarily for seasoned clinical research associates (esp. oncology experience)... if we have backgrounds in other fields with other talents, figure out how its transferable into the arena Positions: numerous positions across all functional areas (data science, stats, marketing, legal...) Regionalization: when looking at how to minimize cost, they look at how to regionalize (how to have sites anywhere in the world and minimize travel costs... sponsor CROs higher regionalized staff)

Close out visit: sponsor responsibilities and perspective

Monitor = main character before going to property, review queries: -status of queries for that site (database lock can NOT occur until all data is cleaned!) -all queries must be completed with no questions left behind -monitor could look into the system from their home base before going to site (to see status of queries) Review previous trip reports for outstanding issues: ex... -document that they could not find -follow up to some type of medical procedure that patient has undergone -outcome of AE -to ensure that there is full reconciliation of drug (that was not completed at last visit) Review pending hospitalization/adverse even reports -patient may be off on holiday and experience AE, go into ED, generate a record... when they return to trial site they need to tell coordinator, who needs to follow up with agency to gather data (patient has to give permission to coordinator first! - can take long time) Confirm full drug reconciliation!!! -do not close site prior to this Monitor needs to be assured all drug has been returned, or at least follow up (about why it hasn't been returned) **no further questions before monitor seals up the box to send the drug back/destroy it on site Review policy materials! -publication responsibilities of the PI -process for how sponsor allows data to be published from the results at this site (for future publications) ***make sure well explained so no question later on/lead to breach of info

QA

Quality Assurance

Title 21 - Code of Federal Regulations

Regulations in 21 CFR specific to auditing: -part 50: protection of human subjects (informed consent process and required criteria) -part 56: institutional review boards (composition and purpose of IRB) -part 312: investigational new drug application (sponsor and investigator obligations) -part 314: applications for FDA approval to market a new drug (components that a new drug must follow: safety reporting and sponsor obligations) -part 11: electronic records; electronic signatures (ensures that electronic signatures are as valid as hard copy signatures) -part 58: good laboratory practices for nonclinical laboratory studies (components for animal welfare and stability testing)

Close out visit: Sponsor Responsibilities and Perspective

The site and sponsor have the same goal in mind: getting drugs, biologics, or devices to market to help our patients. There are different priorities for each group (diff responsibilities)

Targeting consumer example: detergents

Tide for consumer A: "detergent that helps keep everyday laundry looking clean and new" Era for consumer B: Detergent provides powerful stain removal and pretreating for physically active family Cheer for consumer C: detergent helps protect against fading, color transfer and fabric wear with or without bleach Ivory snow for consumer D: provides mild cleaning benefits for a pure and simple clean Dreft for consumer E: helps clean tough baby and toddler stains **each target to different groups... all actually P&G brands. companies often develop different offerings for consumers with diff. needs

Sample TOC for study protocol

Title page Protocol synopsis 1. intro 2. study objectives 3. study plan and procedures 4. measurements of study variables and definitions of outcome variables 5. data management 6. statistical methods and determinations of sample size 7. study management 8. ethics 9. procedures in case of emergency, overdose or pregnancy 10. references

Puffed star activity

What could have made it better? (root cause of problem) -more training -more clear instructions -helpful video -provided measurements CAPA: Corrective Action and Preventative action

Quality in Clinical-Regulatory Documents

absolutely essential to have QUALITY documents Quality... how do authors and reviewers consistently achieve high quality in all docs? -there are generic communication standards and processes for the efficient and effective production of clinical-regulatory documents -these standards are described by 7 principles that fall into 2 main themes: 1. How to define document quality -each doc has specific purpose and should be produced with purpose in mind -no clinical regulatory docs should be produced in isolation, but should link to others (clinical continuation continuum) -team must meet at specific times to agree document content and format -a clear comm. strategy developed -docs must be critically reviewed by appropriate experts -finalization of docs should only occur after consensus of document quality has been reached by appropriate experts and people signing the docs 2. How to achieve document quality

Sample CSR TOC (2): results section

after you've evaluated how well you've met study objectives and how well you've carried out instructions of study... now you look at data and what it tells you. look at study patients, demographics, protocol deviations, treatment compliance, any addnl. meds, series of conclusions about study patients. if you've done job well, those conclusions will say "study population representative of broader population expected to take drug" efficacy, pharmacokinetics... did we meet objectives? ends with series of conclusions on those two things. hopefully results say that drug was efficacious and EPK parameters what we expected. Safety results section... summary of safety, extent of exposure, adverse events, deaths/SAEs, discontinuations... analyze clinical lab evaluation, VS and ECG findings, any other safety observations... concluding statements of safety of the drug and what these results show us Overall discussion that pulls together everything into study report... what is the take home message from this study? did we meet the objectives or did we not? along with any info/conclusions that might have come out of study end with reference list and section with all tables, figures, graphs that didn't make their way into body of the report

Quality assurance

all planned systematic actions established to guarantee that the study is being conducted and that the data are generated, documented (recorded), and reported in compliance with GCP and the applicable regulatory requirements

Sponsor

an individual, company, institution, or organization responsible for initiating, administering/controlling, and/or financing a clinical study

Certified Audt

audit accompanied by a declaration of the auditor confirming that the audit was conducted (not all companies produce a certificate, but many do as evidence that an audit was conducted INSTEAD of submitting report to RAs)

CFR

code of federal regulations

CRO

contract research org

CAPA

corrective action and preventative action

Clinical Trials Website (CTW)

database for clinical trials Debate in media over perceived lack of disclosure of clinical trial data by pharmaceutical industry (people thinking companies not releasing data that would make them look bad... only good stuff) -calls for info to be made available at time the trials were initiated or publication of trial data in peer reviewed journals not allowed -this means many pharma companies now have to disclose their info on CTWs, but also place info on the US gov website after drug approved (www.clinicaltrials.gov) -calls for clinical trial info to be made available to the public at the time the trials are initiated, or publication of trial data in peer-reviewed journals not allowed

Audit document

documentation that makes it possible to reconstruct the events

A closer look: the Ketek case study

example of an outcome that could have been prevented/minimized -remember, when a regulatory agency or board of health conduct a regulatory review, it is called an "inspection" FDA form 483 -issued if there are findings observed -to the firms management or sponsor at conclusion of inspection -observed any conditions that were considered violations -the purpose of FDA form 483 is to notify the company's management of objectionable conditions -discussed with companies management at conclusion of inspection -each observation read and discussed FDA field inspector will submit the finalized form to his/her supervisors -FDA full warning letter may be issued depending on severity KETEK WARNING LETTER -mentions that audit visits did occur and issues/observations found -no corrective or preventative action followed through -failure of sponsor to maintain oversight of the investigator site and the study -many red flags... audit did pick up on them... sponsor did not follow through to make sure corrective action occurred -warning letter to sponsor, investigator was inspected by FDA and faced disbarment, indited on fraud (guilty and sentenced in prison)

types of regulatory audits

follow categories set by regulatory agencies (FDA, ICH) -Good manufacturing practices (GMP -GCP -Good lab practices (GLP_ **US mostly focusing on GCP (included in GCP is PVs = pharmacovigilence audits)

Review best practice: how to perform strategic review

form expectations: -form expectations about purpose and content before reading the doc review: -review against other documents in CCC -review against the core standards for that document read in a non-linear fashion -(not starting at page one and reading through like novel) -open it randomly! if you can't get a sense of what its trying to tell you at that point... its not well written -reviewers are going to review their area of expertise (jumping around) look for issues: -look for mistakes or things that don't make sense -if questions are raised, answers should be near by evaluate the quality: -evaluate the quality of the support for the label -this document should support certain parts of the label

GCP

good clinical practices A standard for the design, conduct, realization, monitoring, auditing, recording analysis, and reporting of clinical trials that provides assurance that the data the reported results are credible and accurate and that the rights, integrity, and confidentiality of the trial subjects are protected

Review Best Practice: types of review

impossible to perform 2 types of review simultaneously (effectively)! Strategic Review: -focus on evaluating how well the doc supports the proposed strategy for development -usually done by checking internal consistency against other docs in communications continuum Inspirational review: -focus on correcting factual errors, poor grammar, typos, mistakes in format...

ICH

international conference harmonization

Document publishing: the end of the line

last thing that happens before submission assembled and shipped the health authority complex process that includes (but not limited to): -assemble and publish regulatory clinical documents that meet submission-ready standards in an ER/ES (electronic records and signature) compliant environment -study protocols, amendments, amended protocols, statistical analysis plan, investigator brochures, clinical study reports, IND annual reports, submission documents, etc -add bookmarks and hypertext links to PDF documents as well as compiling submissions in eCTD format not a push of a button! should not be underestimated

Common technical document

pyramid of common technical document (CTD): CTD - when a company wanted to submit an NDA in the US, there was one set of requirements for that submission -if company then decided to submit MAA in EU, that submission looks completely different than what was done for FDA... and a submission to Canada would look different too -CONFLICTING REQUIREMENTS: production of a submission was a very work intense and detailed proposition -CTD came out of ICH work... harmonization! means all of us getting along and following the same script -pyramid is exactly that Base of pyramid: all individual study reports (clinical, non-clinical, quality reports are the basis) -protocol for each study included as appendix to that study report Sitting about base (mid level): various summaries, overall quality summary, clinical overview, non-clinical area Sitting above that: introduction to the entire submission and submission TOC sitting on top of that in module 1: is the label and any regional administrative information WHY IS THIS IMPORTANT? -Common technical document takes the challenges away of varying requirements -all countries signed onto ICH follow this format CLINICAL MODULES (bottom right 3) -all the clincial study reports and associated protocols are the base upon which the submission is built -sections specifically about efficacy, pharmacokinetics, and safety -bottom right = Module 5 aka Clinical Study Reports -just above that is Module 2.7 = Clinical summary (broken into 4 major documents: module 2.7.1 summary of biopharmaceutics, 2.7.2 summary of clinical pharacology, module 2.7.3 sumary of clinical efficacy, module 2.7.4 summary of clinical safety -all of those summarize the specific type of data from all of the study reports that make up the submission -ex: "in short, here is the sum total of the efficacy for this project" - summary of clinical efficacy, or module 2.7.3 -BE CAREFUL to understand that the clinical summary is a factual presentation of data, NOT a place where the medical communications professional or anybody else on the team tries to make sense of what it means (not interpreting data at this point) -Above that is Module 2.5 Clinical Overview (place where all of that interpretation happens)... presented in 2.7 and interpreted in 2.5 -subsections in clinical overview (biopharmaceutics, clinical pharm, efficacy, and safety) Module 5, 2.7, 2.5 all pooled together... then put with non-clinical info and quality info... pooled to module 1/label for what ever country you're marketing in -sum of pyramid is sent to regulatory authority, and that sum total is called SUBMISSION -medical communications professionals work on every document in clinical communications continuum... everything benefits from medical professionals expertise

QC

quality control the operational techniques and activities carried out within the quality assurance system to confirm that the quality requirements of the activities related to the study have been met

Site close out: documents and final task review

regulatory documents in site master file (that study coordinator needs to review before monitor shows up for close out visit): -administrative binder -all IRB and FDA documents (regulatory and ethics committee) -final financial disclosure (several times when PI and others must submit financial disclosures of any potential conflict of interest) (NEEDS to be reviewed/ensure compliance) -delegation logs (times when PI delegates tasks appropriately... has to be noted on delegation log!) -updated CVs and staff member changes (may need to update throughout the study) -storage of documents (site personnel let monitor know where documents should be stored) -estimate time for final query resolution -when will results be available? where? who will receive first? -when unblinding occurs after the analysis of data, how will there be notification to patients? (usually sponsor provides broad process... up to the site to communicate!)

SOP

standard operating procedure detailed written instructions to achieve uniformity in the execution of a specific function mandated by regulation and guidelines that companies have SOPs (especially when conducting studies)

Situational analysis (SWOT)

strengths, weaknesses, opportunities, and threats -allows a company to understand where it stands (internally) and better understand its market and competition (externally) -identifies factors that can positively or negatively impact success -helps develop and provide support for organizational goals

Site close out (coordinator responsibilities cont.)

study coordinator needs to prepare in advance and have ready to provide the monitor all the signed ICFs of ALL study subjects at their site. -at the end of the study, it may become obvious that a pt still in the study (amendment to protocol) updated ICF was not signed yet! -this is why before site close out visit it is the responsibility of study coordinator that these patients are contacted and gaps are dealt with -coordinator needs to ensure that ICF process was documented in source documentation (so that when monitor shows up, all easy for monitor to check) -Ethics review board needs to receive notification and outcome of this site (for what happened during the study) -copy of ERB notification and study summary given to monitor after the visit -coordinator needs to go through site files and make sure they're complete (no inconsistencies) -confirm drug inventory and reconciliation completed for return to the sponsor (last time things can be answered if found something in pt record!) i.e. dosage/compliance

Sample CSR TOC (1): Methodology

study has been conducted, patients enrolled, data collected... now ready to report the study out this slide shows major headings/subheadings, similar to protocol. this is on purpose because first part of study report relies heavily on protocol. a lot of the info will be repeated from the protocol. perhaps not word for word but gist of it and major messages appear in the FIRST PART of study report. full protocol will appear as one of the appendices of study report

Inspection

the act by a regulatory authroity of conducting an official review of the documents, facilities, records, and other resources that are deemed by the authority to be related to the clinical study and that may be located at the site where the study is conducted, at the facilities of the sponsor and/or of the contract research organization (CRO) or at other sites that the regulatory authority consider appropriate

Audit report

the auditor's written evaluation of the results of the audit for the sponsor

Regulatory Authorities

the authorities for drug regulation. these can be agencies with the power to regulate. in the guidelines for good clinical practice of the ICH, the term "regulatory authority" is used to designate the authorities that review the clinical data submitted and those that conduct inspections. AKA responsible authorities

Close out: Site responsibilities and perspective

what sites need to do to meet requirements of the sponsor and ensure all processes and procedures were followed: PREP: (study coordinator key individual to ensure all tactical items are completed for close-out visit) -coordinator needs to prep! -ensure all investigational product (IP) is accounted and ready to be returned to sponsor -reach out to patients to return IP, do inventory and reconciliation of it (prior to close out) -if monitor has to send unused drug back, its helpful for coordinator to help the monitor by obtaining boxes/tape/shipping supplies -check the status of all queries, whether outstanding or completed (further investigation may be needed) -look at the previous trip reports or notes for outstanding issues (were there previous things that monitor asked for clarification on?) -make sure hospitalization or adverse event reports are available for the monitor (if not... they need to reach out and have it provided when monitor is on site) sponsor AND site in partnership... mandates that both parties need to take responsibilities and follow through

FDA Modernization Act (FDAMA) of 1997

why do companies go through all that extend of providing all that info?? at least one answer is in the FDAMA of 1997 This act focused on reforming regulation of food, medical products, and cosmetics. Reauthorized the prescription drug user free act (PDUFA). And most importantly, provides for an expanded database on clinical trials which will be accessible by patients. -With the sponsors consent, the results of such clinical trials will be included in the database. -Allows a firm to disseminate peer reviewed journal articles about an off-label indication of its product, provided the company commits in itself to file, within a specified time frame, a supplemental application based on appropriate research to establish the safety and effectiveness of the unapproved use -AKA think back to label... used for specific use... frequently doctors say "I know that this drug is not used/approved for another condition, but I think it might do the trick" and they prescribe it anyway (off label use!) -Companies CAN NOT promote off label use -FDA modernization act allows for supplemental application to show safety/efficacy

Generic CSR Production Times

wow, that's a lot of writing... production of study report is broken down into discrete steps. varies depending on company. but generally process is the same: 1. Before database locks, a prototype of report is produced (3 weeks), reviewed by all staff. agree that non-data driven sections are done correctly... proposed way of presenting study data makes sense... then it has approval of study team. done 1 MONTH before database lock 2. database lock: -data cleaned, analyzed 3. production of draft data (2 weeks), then reviewed, any comments/suggestions 4. final data/analysis available (2 weeks) 5. initial draft report written (3 weeks): take prototype developed earlier and actual data is put into the study, report is populated, and any conclusions or discussions is put into report 6. draft review by broad cross functional team (1-2 weeks) 7. comment resolution and final draft meeting (1-2 weeks) -some type of resolution agreed upon after talking through issues -resolution may be that we're not accepting a comment 8. final review (1 week) -takes all those comments, incorporates them and produces final draft of study report -given a final review, 9. comment resolution meeting and final report: (3 days) -another resolution meeting, then document approved and sent to publishing 10. publishing and sign off (2 weeks) A lot of pressure to reduce that time frame (16 weeks currently to produce a signed off clinical study report)