Wednesday, December 30, 2009

Data Management for Clinical Studies

The management of data at the clinical study level is the foundation of what will eventually become one of the many building blocks of your clinical submission to FDA. Considerations that must be processed and planned by regulation and guideline regarding FDA, EMEA, ICH, TGA, DEC, other, must be current in compliance and compatible and equivalent to pharmaceutical industry standards. Engage experts to manage your data - it is impossible to do otherwise and achieve the integrity of data and accuracy that is required by regulation. At the Clinical Study Level, there are steps in "handling" data, from CRF development to Database Lock to Database and Program Transfers at the end of the clinical study.

Here are important steps and points to consider, and without question, each step and/or action must be recorded, processed and managed by quality management data plans specific for the task - all of the following require "Standard Operating Procedures (SOPs)". On FDA Audit, for sure, these plans must be available for review by the agency. Each respective plan must include data handling versions specific for each task, as reviewed below.
  1. CRF Development.
  2. Database Setup - "Oracle" is the choice and CDISC versions 2.0 and 3.1 are used by pharma at this writing and are compliant with regulatory standards and compatible with industry use and FDA review.
  3. Data Validation.
  4. Data Coding - The management of data for clinical signs and symptoms, AE coding using MedDRA Version 9.1 or previous versions. Treatment Coding using WHODRL Version 6.4 or previous versions. Pharmacovigilance database reconciliation.
  5. Quality Control Management Procedures for Interim Data Analysis (IA), Data Entry Audits, Data Review, Data Change, Database Lock and Data/ Program Transfer at the end of the Clinical Study. Data/Program Tranfers can be formatted in .sas., csv., txt., xml, other - the format must be agreed upon by the pharma, all CROs, FDA and WW agencies slated for submission.
  6. Quality Control (QC) Plans to ensure accurate, compliant data. Expert QC teams work with raw data captured in the CRF, DCFs, listings, PPs, other source data documentation to ensure correct management and accuracy of data until the database is locked and the data is transferred to the sponsor or to the next step - the clinical submission team.
  7. End of Clinical Study Data Management.
  8. Data Tools - Clinical Data Management "Systems" that are used by the industry and compatible and compliant with FDA 21 CFR Part 11 Guidance. For example, "Capture System", Version 5.5, Editor "Clinsight".
  9. Audit Trail Systems and SOPs to capture all data changes, database actions and data and procedural change and standard deviations.

Expert data management teams work onsite and offsite and integrate with the sponsor, the CROs, the monitors and clinical study site personnel, CRC, CRA, PIS, sub-PIs, from the first data point - and from CRF development to end of study transfer of data and programs. Monitor and Track Data. Develop Plans. Adhere to Plans. Record Changes. Manage Change. Lead the team and manage the plans.

Sunday, December 27, 2009

SAS Programming Points to Consider in Clinical Submission

Remember, there is SAS programming performed at two levels in a clinical submission.
  • One: There is programming which occurs at the clinical study level. At the completion of all clinical studies, each clinical study database is reviewed, cleaned and closed. Each clinical study SAP (Statistical Analysis Plan) will direct the generation and programming of clinical study TLGFs - SAS output of programmed tables, listings, graphs and figures to be incorporated intext and EOT (End of Text) located in the appendix of the CSR.
  • Two: At the completion of the last pivotal clinical study or before, depending on the MSPP, and according to an Integrated, Global SAP, a GIDB (Global Integrated Database) is created which integrates all data from all clinical studies, in particular for clinical safety, clinical efficacy and clinical pharmacology. SAS programming off the GIDB will serve as the data source of integrated TGLFs that will be used by medical writers and clinical team members to develop CTD Module Clinical Summaries (2.7.1, 2.7.2, 2.7.3, 2.7.4), Clinical Overview (2.5.), ISS (Integrated Summary of Safety) and ISE (Integrated Summary of Efficacy. Note: There is a separate, additional ClinPharm Database at the Global Integrated level of programming.
  1. All clinical study databases and the GIDB must be CDISC compliant for the year the filing is to be submitted to FDA.
  2. It is strongly recommended that Subject or Patient Profiles (PP) are developed and programmed for Clinical Phase 2 and 3 studies. With communication and logic, FDA will negotiate with the sponsor to program PPs only for pivotal Phase 2 and 3 clinical studies, refer to the Integrated SAP as to whether the programmed TLGFs will be pooled in some way, for example, for Phase 2 and 3 clinical studies, data is often combined.
  3. Before creating the GIDB, CSR databases must be validated and checked for quality, accuracy, consistency, completeness, coding, compliance, nomenclature, CDISC version, etc. The GIDB must be harmonized when combining databases from all clinical studies worldwide. Standards, metrics, terms, units, calibrations, measures must be standardized for labs, AEs, medical history, eligibility, etc.
  4. FDA will most certainly ask the sponsor to submit a ISS (Integrated Summary of Safety), which is similar but not exact in content and data presentation to CTD M 2.7.4, the Clinical Summary of Safety.
  5. FDA will most certainly ask the sponsor to submit a ISE (Integrated Summary of Efficacy), which is similar but not exact in content and data presentation to CTD M 2.7.3, the Clinical Summary of Efficacy.
  6. TLGFs for CTD Modules 2.7.3 (CSE), 2.7.4 (CSS) and the ISE and the ISS, respectively, will be programmed in SAS output from the GIDB.
  7. All document summaries, all PPs, all CSRs, all TLGFs, whether at the clinical study level or the GIDB level must be QC. Quality Control of data is essential at the CSR and GIDB levels.
  8. Remember that the ISS, ISE, CTD Module GIDB TLGFs must be compliant and compatible with the clinical submission writing system and "que" and the publishing tool, especially for format considerations.
  9. All GIDB SAS programs are submitted at the time of filing to FDA for Phase 2 and 3 clinical studies and ClinPharm studies.
  10. If requested, Phase 1 SAS programs are also filed at the time of the clinical submission with FDA.
Much more to come...

Saturday, December 26, 2009

Clinical Submission - Integrated Statistical Analysis Plan (SAP)

For your clinical - regulatory filing, FDA requires an integrated SAP. An integrated SAP is a harmonization of data and terms, data coding, data guidelines, data requirements, data CDISC version and data otherwise of all clinical studies for safety, efficacy and clinical pharmacology, performed during the clinical examination and lifetime of the investigational drug. The Integrated SAP must be compliant and up to date with all requirements and guidelines for the year the file is to be submitted to FDA.

It is strongly recommended that at the completion of your Phase 2 studies, a Briefing Document is prepared for FDA that will include the overall Submission "Integrated" SAP and Analysis Plan for the following:
  • Develop a Integrated Clinical Submission SAP for Clinical Phases 1,2,3
  • Choose how the Integrated Safety Data will be presented and then develop your Integrated Safety SAPs accordingly - for example, a SAP for Phase 1, a SAP for Phase 2, a SAP for Phase 3, or a SAP for Phase 2 and 3 combined
  • Develop a separate Integrated SAP for Efficacy - usually pooling Phase 2 and Phase 3 clinical studies
  • Develop a separate SAP for Clinical Pharmacology
  • File the SAPs early with FDA as a component of the sponsor's End of Phase 2 Briefing Document
  • Request a date with FDA to review and comment and discuss the End of Phase 2 Briefing Document especially the SAPs
  • Make sure to finalize agreements with FDA on the SAP methodology early so preparation for the Integrated Global Database , the GIDB can begin
  • DO NOT unblind the last Pivotal Phase 3 Clinical Study before finalizing and receiving agreement on the Integrated SAPs for Safety, Efficacy and Clinical Pharmacology
  • Ask FDA for meeting minutes pertaining to the End of Phase 2 Briefing Document Meeting to ensure comprehension and confirm agreements of what is to be filed pertaining to data presentation, integration and pooling
  • Review the meeting minutes and debrief notes and all correspondence from FDA - it is important to archive all correspondence from FDA - follow the correspondence and make sure that all items of the correspondence from FDA are addressed - if this is not done - a RTF - REFUSAL TO FILE will be triggered by FDA at the time of filing - the RTF will be issued for "filing an incomplete clinical submission". Ramifications, costs, loss of timelines, submission integrity, questioning perception with FDA and delays are huge and can be easily avoided with properly managing FDA correspondence and follow-up.

Wednesday, December 23, 2009

Effective Medical Writing for Clinical Submission #6

For medical writing for clinical submission to be effective, lets review submission reminders and points to consider:
  • Know FDA and all regulatory requirements and guidelines to ensure a complete and compliant document
  • Always remember who your end user is - yes, FDA and regulatory agency reviewers, so create a simple, user friendly document
  • Communicate to FDA and others, planned changes that may be used in a document - if different from the standard requirements and guidelines
  • Again, provide user friendly documents that are easily navigated
  • Make sure all bookmarks, hyperlinks, internal (text) and external (linked) to the document are present, correctly linked to content and are active
  • For the CTD Module 2.5, which is the Clinical Overview and for the Application Summary for a NDA, transparency goes a long way, discuss weaknesses in the subject matter and content as well as strengths - be prepared to address both in support of the benefits (risks) of the drug
  • Respect document length (# of pages and # of in text and end of text (EOT) tables, listings, graphs and figures), especially the Clinical Overview - the overview must be ~25 pages summarizing data and interpretation - not a regurgitation of tabular and text table data
  • Ensure appropriate hyperlinking to other CTD Modules 1,2,3,4,5 and/or NDA Sections such as, the ISS (Integrated Summary of Safety) and ISE (Integrated Summary of Efficacy).
All clinical submission documents have a respectful, anticipated and expected length - adhere to the requirements and guidelines when determining the length of all clinical submission documents early in the development of the document. The "recommended" length of each clinical submission document can be found at

Sunday, December 20, 2009

Effective Medical Writing for Clinical Submission #5

Yes, there is the document type and the timelines to consider, now lets look a bit more into the review and QC cycles involved in the development process of the document.
Important points to consider:
  • Clearly define the objectives and the process to be followed during the actual review and QC
  • Who on the clinical and project submission teams are involved in the review and the QC - of course the medical writer and the QC data controller are involved throughout the lifetime of the document under development
  • How many review cycles are needed
  • How many QC cycles are needed
  • How will the review comments be tracked
  • How will the review comments be resolved
  • Who will resolve the review comments
  • Check to see if the review comments are implemented and implemented correctly
  • Follow the same considerations for outlining the process for QC comments
  • For each review and QC cycle, no comment should be left without resolution - this includes, data, text, statement, interpretation, conclusion or an action item
  • Submission medical writers and QC data consultants must always interact directly with clinical or expert decision makers in resolving comments and QC findings - this to avoid uninformed intermediaries that may not have credible, accurate, decisive resolutions to positioned comments.
In order to move a document ahead, each review and QC cycle must not leave open-ended comments and both medical writer and QC consultant must be able to close out the comment, complete the resolution and implement the change to the document - by using a tracking tool which archives the change, the reason for the change, the source of corrective action, date of change, the version of the document changed and of course the data changed - the comment is then signed off and initialed by the MW and QC. The comment is not to be revisited. The next document will reflect the implemented correction.

Moving the document ahead with Quality is essential. Changes must be tracked and resolved. Lead the team and manage the comments, track the resolutions.

Saturday, December 19, 2009

Effective Medical Writing for Clinical Submission #4

When preparing clinical submission documents two parameters must be considered. One, the document itself and two, document timelines. The latter is in some instances more important and more difficult to achieve. Yes, the document must be completed according to GCP, ICH, FDA and CTD requirements and guidelines. However, the document must be completed with a timeline in mind as well. This timeline is integral to the rest of the clinical submission because the message and content of each document builds on each other as the writing team climbs the clinical submission pyramid, from CTD Modules 3,4,5 being the foundation of the clinical submission pyramid, Module 2, backbone and Module 1, the peak of the pyramid.

Important points to consider with clinical submission document timelines - what the clinical, project submission and medical writing teams must develop and adhere to for each document prepared and written:
  • Are the document timelines realistic
  • Implement periodic clinical and medical writing team meetings to ensure that the timelines remain realistic
  • Implement measures to communicate the progress of each document vs timelines
  • Ensure that each medical writer and quality data controller gets accurate, quality source documents to develop the document content
  • Ensure that each medical writer and quality data controller gets accurate quality tables, listings, graphs and figures (TLGFs) to develop the document content
  • Ensure that each medical writer and quality data controller gets source documents and TLGFs on time for a start date to begin writing - the clock starts
  • Ensure that each medical writer and quality data controller gets a complete set of source documents and TLGFs
  • Ensure that each medical writer and quality data controller gets the correct, most up to date version of the source documents and TLGFs
  • Build in useful, meaningful and appropriate team reviews
  • Build in useful, meaningful and appropriate cycles of QC
  • Build in a realistic sign-off final date.
Monitor and project manage each document and each step of document development vs a timeline.

Measure metrics on completion vs progress and impact to the overall timeline of the clinical filing and clinical submission. Lead the people, project manage the documents, control the quality of the data. Keep timelines realistic. Ensure timelines.

Sunday, December 13, 2009

Effective Medical Writing for Clinical Submission #3

Focus, create and develop templates early and communicate processes and procedures to medical writers and all team members. Submission medical writers who are experienced must lead this effort since they have the ultimate responsibility for the overall quality of the final document. The direction is simple and if followed religiously, the final document will be content final, with accurate, consistent data, ready for publish, ready for submission, ready for FDA.
  • Focus all writers, all teams, nonclinical, clinical, CMC, CP, CRO, Sponsor, Outsourced Submission Teams, etc., early in the development of the submission document pertaining to agreed upon processes and procedures
  • Adhere to the processes and procedures - do no deviate - if a deviation is considered, quickly inform all team members - the deviation will undoubtedly impact subsequent documents
  • Work with Outsourced Quality Control consultants early in the process to ensure accurate document versions and data versions across all functions, across all documents
  • Establish an agreement on a storyline early in the development of the submission document
  • Do not deviate from the agreed upon storyline once set and communicate the storyline to team members and medical writers - this storyline will be written in numerous documents and cited often in the overall submission - stay with one storyline for consistency and to drive the benefits of the drug to the reviewers at FDA
  • Create submission documents shells early in the development of the TOC - documents shells, populated with data or not, can provide useful information pertaining to electronic hyperlinks, size of submission, how many programmed tables, listings, graphs and figures per document, how to provide submission document and content crosslinks, etc.
  • Develop the submission document format, writing styles and submission and publish ready templates early and consistently across all submission NDA Sections and CTD Modules 1-5.
Good medical writing and good, clear, concise content - is a team effort. Communicate. Enforce Quality and Consistency Processes and Procedures. Track and review the progress of each document frequently. Lead the submission team and project manage document issues!
More to come...

Friday, December 11, 2009

Effective Medical Writing for Clinical Submission #2

Once the clinical submission team establishes (with FDA) a TOC for the clinical filing, responsibilities and accountability's are assigned to medical writers. Who will write which documents? Will the documents be written by the sponsor? Will the documents be written by the pharma's functional areas? Will the documents be written by the CRO? Or will the documents be written by consultants, members of a high level medical writing project/clinical submission team asked to participate (outsourced) by the pharma?

It is strongly advised that writing decisions and assignments do not change mid-stream - adhere to a decision that there is one author - and that author is responsible and accountable for each assigned document from start to finish, submission ready, publish ready through final sign-off.

Simple considerations to establish early...
  • Who is responsible from each function, if a function task, if a consultant, if a medical writing team?
  • Who is accountable from each function, if a function task, if a consultant, if a medical writing team?
  • Establish clear reporting and responsibility lines of communication, for data questions, for issues, for progress, for status!
  • Clarify writing responsibilities, who will write, who will review, how many reviews?
  • Clarify who will QC, who will review the QC findings, who will implement the QC findings, who will track the QC findings, how to track the QC findings, how many cycles of QC?
  • Clarify ownership of the documents as a whole, to ensure consistent, data accurate, submission ready, publish ready, template accurate, storyline correct, documents with continuity and completion endpoints!
In my opinion and historically, since clinical submission documents are frequently complicated with data, hyperlinks and statements, outsourced medical submission writing teams should be engaged by the pharma - these medical writers must be leaders in the respective subject, be proactive (and diplomatic) in soliciting information from sponsor functions, which include but are not limited to, biostatistics, project management, data management, nonclinical and clinical functions, CROs, experts and QC. The medical writer drives the document to completion not clinical or regulatory team participants. The medical writer must work early in the development of the document template with programmers, QC and submission publishers to ensure submission ready and publish ready documents at completion and final sign-off.

More to come...

Thursday, December 10, 2009

Effective Medical Writing for Clinical Submission #1

Effective, which means, cost, time, effort, quality-controlled, quality-assured, consistent, accurate, version correct, data-driven, GCP-driven, process and procedure adherent, medical writing for clinical submission will follow these parameters early in the development of a document to be written...

Consider all documents and components, for examples, appendices, narratives, TLGFs, required for the clinical submission...
  • a clinical submission for a drug for example has 5 CTD Modules, "what documents and document components are to be written"? Develop a TOC!
  • a clinical submission will require a format, "what format will be followed"? CTD? Legacy NDA? 505 (b)(1) or (2)? Choose a format!
  • a clinical submission will require source documents to support the written documents, "what are the source documents, which will be included in the clinical submission"? Develop a TOC that reaches this level of granularity!
  • a clinical submission will require a team effort between writers, QC, QA, sponsor functions, experts, CROs, etc., "what is the process for file and information transfer between team members onsite and offsite, inhouse and remote"? Develop a process and procedure! Adhere to the process and procedure throughout the clinical submission! Communicate the process and procedure to all team members!
For effective medical writing for clinical submission, these are important points to consider early in the process.

More to come...

Tuesday, December 8, 2009

Clinical Research Fraud - Prevention

Here are some tips on "How to Prevent Clinical Fraud" to Pharma Sponsors, Clinical Team Staff and CRAs and others who monitor and/or audit GCP at Investigator Clinical Study Sites...

During the pre-study evaluation, carefully scrutinize clinical sites in the following areas:
  • interest in the study
  • stability of the clinical staff onsite
  • investigator/staff interactions
  • workload
  • level of training
  • conduct GCP training at the start and throughout the study as necessary
  • emphasize company policy on fraud at the initiation visit
  • be expert on the protocol particularly with parameters that determine eligibility and primary efficacy
  • minimize the use of enrollment incentives and pressure to perform and enroll
  • don't place needless requirements or unreasonable demands on clinical sites
  • maintain frequent interaction with clinical sites through regular monitoring visits and phone calls.
Good follow-up practices and procedures and early utilization of GCP and quality control measures will undoubtedly provide rigor, expectations of clinical quality and reduce the thought and even the logistics of clinical fraud at the site.

Be involved as a monitor and sponsor. Practice follow-up. Train and insist on integrity and quality control and GCP.

Saturday, December 5, 2009

Clinical Trial Fraud - Questionable Miscellaneous Data

Finally we come to "miscellaneous" data in clinical misconduct and fraud. Miscellaneous data is just that - found everywhere, comment page sections, comment fields, notes, charts, medical history, entry eligibility, etc. There is a trend. If a few miscellaneous data checks are found, for sure, there will be numerous "finds" in data entries and corrections, certainly not according to GCP and Quality Control Audits processes and procedures.

Here are examples of miscellaneous fraudulent clinical data:
  • Miscellaneous items in subject binders incriminating
  • Difficult to determine PIs involvement
  • Reiteration of SC notes
  • Corrections are rarely initialed
  • Corrections are rarely dated
  • CRF Investigator Assessment Page says "not assessed". At a later date, "not assessed" is crossed out and then a reaction is indicated.
  • No "person obtaining subject informed consent" signature
  • Documents are dated and are signed by employee with dates before the 1st day of employment at the clinical study site
  • No GCP training
  • Medical History page lists 1st item as a surgery which occurred several months after the subject's enrollment into the clinical study
  • Clinical chart notes indicate "itching/irritation in TX area". Source documents indicate "none".
Inherent in the trend of miscellaneous data fraud is inconsistency and "forgetting" comments written in a variety of sections and pages during an onsite monitoring visit and/or a subject's scheduled visit according to protocol. Fraudulent data often lacks consistency. Look for the lack of consistency. There is a trail.

Monday, November 30, 2009

Clinical Trial Fraud - Lab Information, General Warning Signs of Misconduct

In my experience, questionable data is readily and easily detected in subject lab information and results. Clinical study staff are trained by education and are expected to know each protocol lab test and understand lab values, IUs and ranges and the proper way to fill out the lab forms. Lab protocols and tests are reviewed extensively during pre-study start Investigator Meetings with staff, monitors and PIs/SCs.

It is my practice as well as my recommendation when reviewing, monitoring and investigating subject lab information and results - do not just log the test...instead, read, read the test and the results, each data entry, read the entire form. A high frequency and incidence of data fraud at the clinical study site will, most definitely, be found in subject lab data.

Where and How?
  • Panic values on labs coded "1" and no comment is made by PI
  • Labs not evaluated prior to entrance into the clinical study
  • Technical units are expressed several different ways by staff and PI/SC.
General Warning Signs of Misconduct - What are these? Easy to identify for a monitor who is clear and present...
  • High staff turnover
  • Staff are disgruntled
  • Staff are fearful
  • Staff are anxious
  • Staff are depressed
  • Staff are defensive
  • High pressure work environment
  • Obsession with study payments
  • Absent PIs
  • Absent SCs
  • Absent staff
  • Lack of GCP training
  • Unusually fast recruitment.
Monitoring with Quality Control is a full time job and when done correctly, GCP is clear and misconduct and fraud are easily seen in trends and such. Choose and interview your clinical PIs, SCs, staff, CRO and/or consultant CRAs/CRCs and monitors carefully. Train them on GCP and QC and QA. Monitor their visits, reports, correspondence, communication and performance.

As well, there is clinical study data that falls into the "miscellaneous" subject data category - interestingly, not significant to subject outcomes or endpoints, but will point a finger at data trends leading to the identification of clinical fraud. These categories will be highlighted in my next blog pertaining to clinical fraud at the clinical study site.

Sunday, November 29, 2009

Questionable Data in Clinical Fraud - Diary, Source Documents

A Diary is a collection of observations recorded by the subject when home. Source documents record the subject's experience onsite, on-study and are data entered by clinical staff. Interestingly, this is an area where misconduct and fraudulent data is plentiful, the subject most of the time has no vested interest in the fraud and will not therefore record untruthful data. Whereas, data entries into the source documents are at the "mercy" of the clinical staff onsite, conducting the study, who may have a vested interest in the misconduct. Often, when FDA performs an unannounced, onsite audit for cause, Subject Diaries are always asked for and reviewed and compared to the source documents, CRFs, etc.

  • Diary states "dose not taken"- dosing record CRF page indicates date taken
  • Diary card information written over
  • Diary and dosing records are out of synch
  • Handwriting is the same for several diary cards
  • Handwriting of SC/PI is the same as writing on the diary cards
  • Date on diary and dosing record is a date that does not exist
  • Subject diaries not collected at each visit
  • Subject diaries altered by SC/PI to match dosing dates in dosing record.
Source Documents:
  • Source document and drug log dates differ
  • Data on source documents not present at previous CRA visit appears at future visit
  • No SAE reported on source documents but an entry added in different handwriting and different ink indicates "except erythyma, edema"
  • Use of pencil in source documents
  • Source documents indicates no PI available to do LSR's that day, yet subject had PE performed
  • PE information in source documents and CRF differ.
During an onsite for cause audit by FDA, FDA inspectors (DSI, OCI Divisions at FDA) come in and have already determined that fraud exists and will confiscate everything related to data or the collection of data at the clinical study site, including computers, electronic data capture systems, hand and pocket data collections systems are well as all paper trails. In some cases, FDA will order biologic samples taken from the subjects on-study to be carted away to a "forensics" lab for future investigation.

Good Quality Control and GCP Monitoring cannot be stressed at the clinical study site. Each clinical study and the data derived from the subjects at each site serve as a building block to the foundation of what will eventually be an integrated global database, a GIDB, leading to a clinical submission to FDA. Clinical studies identified with fraudulent data often are censored from the mix. This often impacts the ability to effectively evaluate the safety of the clinical drug under study as well as subject exposure measurements, efficacy/therapeutic endpoints, clinical summaries of safety and efficacy, benefit/risk statements, clinical summary overviews and the label in the clinical submission. In my experience, and in many cases, data censored at the last moment for misconduct leading to fraud will delay the clinical submission timelines, delay the filing date of the clinical submission and/or FDA may reject the clinical submission in its entirety, a RTF. Several warning letters will be issued, a clinical hold is ordered for the study to halt immediately, while the investigation continues. After the investigation (and data censor) is completed and if the filing of the clinical submission is accepted by FDA - the approvability of the content of the clinical submission, is still in question and is in serious jeopardy for "data quality, non-reporting and integrity" issues.

Monitor, Monitor and Monitor with GCP and Quality Control.

Saturday, November 28, 2009

Questionable Data in Clinical Fraud - Photos, Drug and Supplies

Often the question arises from the sponsor or a concerned clinical site team member - "There is so much data collected per subject per clinical study protocol at the clinical study site, where do we look for questionable data?"

Areas that one may find questionable data are numerous and in my view and years of experience - I can offer hundreds of locations and ideas. As well, I (colleagues) will not be surprised to uncover more areas where questionable data arises in the future.

At this writing, I will share common and not so common areas of questionable data at clinical trial sites suspected of clinical misconduct and fraud, starting with Photos, Drug and Supplies:
  • Photos
  1. Placards indicated different subject numbers but photos are of the same subject
  2. TX area on source documents and CRFs differs from photos - for example cheek vs. back of head
  3. Screening photo shows reaction in TX area - subject already dosing?
  4. Dates on photos do not agree with visit #
  5. Fraudulent photos
  6. Missing photos
  • Drug Log and Supplies
  1. Incorrect subject initials on drug boxes - initials of subject not in our study
  2. Date on drug log and drug box different
  3. No dates dispensed on drug boxes and/or labels in CRF
  4. Drug dispensing log - no entries for several months***
  5. Drug dispensing log indicates drug dispensed, however drug boxes are still in inventory
  6. Date of drug dispensed pre-dated -----after date of audit
  7. Emergency supplies have wrong subject initials on box
  8. Drug dispensing forms were pre-dated.
***At the time/visit on dispensing drug to subjects - the drug dispensing log and forms must be filled out at that time. This is GCP regardless of misconduct. This is true for any observation while subject is onsite, on-study. Fill in the appropriate information at the time of that visit - do not wait.

More to come in the next blog - Diary, Source Documents, Lab information.

Friday, November 27, 2009

Strategies for Detecting Clinical Trial Fraud

Monitor the data.
Monitor the monitor.

What do you monitor - what do you ask for when doing an audit? What detection tactics and strategies work?
  • Ask for all subject information (data, docs, records) pertinent to the clinical study:
  1. CRFs
  2. Source worksheets
  3. Clinical charts
  4. Sign-in sheets
  5. Lab requisitions
  6. Shipping records.
  • Accept no copies -
  1. Review originals whenever possible.
  • There is no easy way, don't just inventory and log, use your experience and understanding - Read -
  1. Lab reports
  2. X-rays.
  • Fraud exists, expect fraud on an audit - assume fraud - work backwards.
  • Question data, question and follow "open-ended data", "loose-ends" -
  1. Missing
  2. Altered
  3. Inconsistent.
  • Don't be timid - challenge the site to explain suspected fraudulent data.
  • "Blame-shifting" during onsite audits "for cause" is pervasive.
  • Be suspicious and challenge the investigator and remind he or she that clinical study conduct and GCP sits with them.
  • Find and engage and cultivate "whistleblowers" - pay attention to -
  1. Staff complaints
  2. Listen to grievances
  3. Establish rapport be approachable
  4. Follow your leads
  5. Don't stray from the data - the data is the data
  6. Watch for changes in clinical staff behaviors
  7. The list is endless.
GCP is well documented and simple to follow - unless there is serious intent to do otherwise. Detect clinical fraud early in data at a clinical site. The ramifications of doing so saves time and perhaps the integrity of the clinical study and/or clinical submission but most importantly protects subject safety, for those subjects that are real.

Clinical Research Fraud - Investigator Data Identifiers

In my experience, clinical research fraud is pervasive and can be found in many subject data collection systems, source records, subject test results and visit documentation entries at the investigator's clinical trial site. The following are the most common data identifiers:
  • Implausible, impossible, in my view, trends and patterns:
  1. 100% drug compliance
  2. Perfect efficacy responses for all subjects
  3. Identical lab results
  4. Identical ECG results
  5. No SAEs reported
  6. Subjects adhering perfectly to visit schedules.
  • Clinical site data not consistent with other centers (statistical outliers)
  • Perfect diary cards, immaculate subject CRFs
  • All source records & CRFs completed with the same pen
  • Source records lack an audit trail
  • No signatures of persons completing documentation
  • No dates of persons completing documentation
  • Subject handwriting inconsistent across documents (consents, diaries)
  • Subject signature inconsistent across documents (consents, diaries)
  • Questionable subject visit dates (Sundays, holidays, staff vacations)
  • Impossible events (eg, randomization before drug delivery)
  • Data contains "digit preference"
  • Subject visits cannot be verified in the medical chart, appointment schedule or billing records.
How to avoid clinical trial site, staff and investigator fraud?

How to uncover data identifiers?

  • Monitor data.
  • Monitor data.
  • Then Monitor data again.
  • Monitor the Monitors.

Thursday, November 19, 2009

FDA - Consequences of Fraud

The consequences of fraud are pervasive, outreaching and forever. If the Sponsor is found guilty of fraud as per FDA, data validity is compromised and the clinical submission is jeopardized. If the Investigator is involved in the fraud, he or she is disqualified, listed, given fines, incarcerated, incur tremendous legal expenses, he or she has just ruined their career. If the Institution, a Hospital, a Phase 1 Facility, a Clinic, a CRO, IRB or otherwise - is found guilty of fraud - lawsuits. What is the consequence to Subjects enrolled in the Clinical Trial - safety and well being at risk, loss of trust in the clinical trial process, lawsuit.

  • Fraudulent Investigators are often used by multiple Sponsors on Multiple Clinical Trials.
  • Since Investigators are often used by multiple Sponsors on Multiple Clinical Trials, these Investigators will have a broad impact on many clinical submissions made by many Sponsors.
  • For example, a case in mind - Investigator F, was involved in 91 clinical submissions with 47 different Sponsors during the same calendar year.
  • Why? Word gets around that there are Investigators that "want to see their clinical trial site do the best". Which means that prior to selection of that Investigator, he or she understands how to manage the Subject CRF, Subject Informed Consent and Clinical Trial Protocol, for examples, in order to provide the Sponsor with "higher" statistically and clinically significant subject positive outcomes and better endpoints with respect to the efficacy and safety of the drug on clinical trial.
Why does fraud occur and how does it happen? To mention a few of the most obvious reasons:
  • Not enough time
  • Not enough staff
  • Not enough monitoring, frequency or intensity to detail
  • Not enough subjects, so subjects are reused and/or subjects are "made-up"
  • Lack of GCP
  • Lack of the understanding of GCP
  • Lack of training GCP
  • Lack of training FDA requirements and guidance
  • Lack of regulatory oversight
  • Lack of interest and motivation
  • Money
  • Greed
  • Intent
  • Pressure to perform
  • Pressure to publish
  • Pressure from senior management
  • Pressure from piers
  • Pressure from political arenas within medical societies, institutions, associations
  • Pressure from CRO
  • Pressure from Sponsor.
FDA Regulations (original statements and updates), pertaining to ("early") actions that must be taken by the Sponsor when fraud, misconduct and noncompliance are suspected or proven, can be found:

Wednesday, November 18, 2009

Clinical Research Fraud - FDA Definition

What does clinical research misconduct, fraud mean? FDA provides a definition that is clear in message and severity. Clinical research misconduct means falsification of data in proposing, processing, designing, performing, recording, supervising, reviewing, analyzing, collecting clinical research or reporting clinical research results, outcomes and endpoints. The manipulation of data and reporting for a self-serving purpose, usually monetary! Simple!

The FDA uses fraud and misconduct interchangeably and includes acts of omission and commission, consciously not revealing all data and consciously altering or fabricating data.
Fraud does not include honest error or honest difference in opinion. Deliberate or repeated non compliance with the protocol and GCP is considered fraud, second to falsification of data which is more severe in penalty and justice and resolve.

Let us review again who commits fraud?
  • Investigators
  • Study nurses
  • Study Coordinators
  • Data managers
  • CRAs
  • Sponsors
  • Lab personnel
  • IRB staff
  • Subjects.
Yes, it is true. Clinical trial subjects have been accused and found guilty of fraud. The reasons are interesting and the content of another blog.

Average breakdown in % of blame:

CRC - 39
Study Nurse - 17
Hospital - 9
Sponsor - 9
Self - 9
Office Staff - 9
PI or Co-PI - 4
CRA - 4.

Monitor and adhere to GCP. Review and monitor repeatedly. Report Fraud.

Friday, November 13, 2009

Clinical Trial Fraud

You are a CRA, CRC, a member of the clinical trial team, CRO, pharma, sponsor, or otherwise - when you become aware of fraudulent data and clinical practices in a clinical trial - what do you do?
Immediately report your suspicion and findings to FDA. FDA will direct the "for cause" call to the appropriate divisions at FDA - Divisions of Scientific and Criminal Investigations. From here, if fraud is proven, any individual or organization participating in fraudulent activities will be held to the full extent of the law governing such in the judicial court system.

Clinical trial fraud is on the rise again.

Major areas riddled with fraudulent clinical trial behavior:
  • over enrollment of patients
  • faking patient informed consent forms
  • faking patient CRFs
  • faking visits
  • faking lab data
  • under reporting of adverse events
  • no reporting of "early patient withdrawals"
  • no reporting of "lost to follow-up" patient visits.
If fraud is proven, clinical investigators and anyone involved in the fraud will be given heavy fines as well as prison sentences.

Who is at fault?

Principle and co-investigators, clinical team members and organizations.

It is difficult to prevent the intention of fraud - but it is not difficult to identify fraud.

Lack of clinical trial and quality control monitoring allows for the occurrence of fraud.

Monitor. Monitor.

Wednesday, November 11, 2009

Vaccine Essentials

The development cycle of a vaccine is laborious, time-consuming, costly and long. A vaccine is a biologic and is made from living microorganisms. The development cycle is different that a pharmaceutical product, a drug, but does share a similar Clinical Phase Program, Phase 1,2,3 and 4 (post-approval). The Clinical Trial Protocols for each Phase share safety, efficacy and tolerance in a broad sense, but protocol designs are very different in design, objectives and outcomes.

The essentials:
  • Exploratory - in preventing a disease or treating the disease:
  1. to understand the disease
  2. to understand the epidemiological data
  3. to understand the correct antigens to use.
  • Pre-clinical stage:
  1. to assess antigen safety
  2. to select the best candidate vaccine.
  • Clinical Development - all Phases are involved in clinical trials and the 1st lots/batches are produced (clinical batches for trials and industrial batches for compliance):
  1. Phase 1
  2. Phase 2
  3. Phase 3
  • Regulatory Approval - all data from previous stages are complied, summarized, quality-controlled and assured and are submitted to regulatory health agencies for approval.
  • Manufacturing - on an average, it takes just less than 2 years to produce a single batch of vaccine.
  • Quality Control - ~70% of the production time is dedicated to quality control of data, process, procedure, R&D, Industrial Operations and Pharmacovigilance.

Sunday, November 8, 2009

Requirements for a Vaccine Approval by FDA

Vaccine research, development and approval is a process that requires, time, is costly and is complex.
Approval Requirements:
  • Successful review of the BLA for a new indication from FDA
  • Successful review of the BLA for a new indication from VRBPAC
  • An adequate product label
  • Benefit/Risk Statement
  • Safe delivery of the vaccine to the public.
After approval of the license, monitoring of the product, production and announced and unannounced manufacturing facility inspections must continue as long as the manufacturer holds the license for the product.
Periodic Inspections (especially for a newly approved BLA license and manufacturer) will include tests for:
  • potency
  • safety
  • purity
  • submission of samples from each lot
  • continued quality control documentation
  • continued quality assurance documentation.
After a period of successful test results, FDA CBER, may determine that lot to lot samples are not necessary. FDA CBER may determine that an alternative procedure is acceptable instead of lot to lot sampling. Lot release protocols showing results of applicable tests for example can be submitted instead. The change from one procedure to another must be in writing and documented with the manufacturer, FDA CBER, and the pharma sponsor. The change will only be granted after a long period of successful routine testing of lot to lot samples.

What's next?

Potential adverse events (AEs) cannot be anticipated, therefore there "will be" a committed Phase 4 pharmacovigilance program as well as VAERS, a Vaccine Adverse Event Reporting System to identify problems after marketing begins. Who is responsible for any problems, manufacturing, safety, AE or otherwise ? - the pharma sponsor. Monitor the Phase 4 program, monitor safety, monitor AE Reports, monitor the Phase 4 monitors, monitor manufacturing, monitor quality.

Friday, November 6, 2009

Vaccine Approval Cycle - Hard Facts to Consider

The Center for Biologics Evaluation and Research (CBER) is the division at FDA that receives and reviews vaccine applications in the US. The regulation for vaccine products in the US can be found in Section 351 of the Public Health Service Act and specific sections of the Federal Food, Drug and Cosmetic Act.
  • The development of a vaccine follows the same general pathway as for drugs and biologics.
  • Pharma sponsor must submit an IND - Investigational New Drug application to FDA.
The IND describes:
  • the vaccine
  • method of manufacture
  • quality control tests (70% of a vaccine's production time is dedicated to quality control)
  • safety
  • immunogenicity of the vaccine in animal testing
  • proposed clinical protocol(s) for human clinical trials.
Clinical Development Phases: (6 - 8 years in humans)
  • Phase 1 Clinical Trials - safety and immunogenicity, 10 - 100 subjects
  • Phase 2 Clinical Trials - dose-ranging, immune response - 100 - 3000 subjects
  • Phase 3 Clinical Trials - effectiveness, tolerance and safety - 3000 - 40000 subjects.
At the end of a successful Clinical Phase 3 development program and if there are no safety concerns or otherwise by FDA, the pharma sponsor files a Biologics License Application (BLA).

The BLA:
  • must provide FDA efficacy and safety information
  • risk/benefit statements and assessments
  • proposed manufacturing facility "actively" in production of the said vaccine when the inspection takes place.
Vaccine Development Cycle:
  • Research & Development - 9 - 14 years
  1. Exploratory - 2 - 4 years
  2. Pre-clinical - 1 - 2 years
  3. Phase 1
  4. Phase 2
  5. Phase 3
  • Registration - 12 - 18 months
  • Product Launch
  • Industrial Operations
  1. Bulk Production - 1.5 - 2 years
Following FDA's review of a BLA for a new indication, the pharma sponsor and the FDA present their findings to FDA's Vaccines and Related Biological Products Advisory Committee (VRBPAC). This non-FDA committee provides FDA with advice pertaining to the safety and efficacy of the vaccine for the proposed indication.

Monitor the Quality (Data), Monitor the Monitor (CRO)

Pharma Sponsor Data Management as it pertains to Quality Management must regularly assess the quality of the data management process and work at the CRO and request data and metrics to track the quality of the Clinical Study Data. Monitor the Quality and Monitor the Monitors who monitor the quality!

Quality metrics may include:
  • frequency of edit checks
  • number of data changes due to data entry error, obvious error and DCF
  • these metrics can be broken down by database and/or clinical study site.
Pharma sponsor DM must review these metrics for any possible trends or inconsistencies in the data.

Where can potential issues be found:

  • edit check programming
  • data entry
  • CRF design
  • data being provided by the clinical study site
  • listings of key clinical study efficacy data
  • listings of key clinical study safety data
  • CRO data entry rules
  • CRO data review rules
  • data being provided by the CRO.
It is the responsibility of the pharma sponsor DM to review these listings for any possible trends or inconsistencies in the clinical study data. Communication of these findings and any recommendations to the appropriate clinical study team members, for example, CRO, Medical Monitor (Pharma Sponsor), Biostatistician, DM, CRA, CRC, must be immediate and have resolution.

Monitor the quality of your data, ensure use of the DMP and QMP, monitor the monitor, the CRA, the CRO, ensure there is verbal communication as well as written metrics and listings providing data, potential trends and inconsistencies. Once found, the action is immediate - correct and assess the impact on clinical study data quality, data error %, resource and capacity to correct.

Most important, communicate the issue(s) to the team, re-train the team pertaining to appropriate use and adherence to relevant SOP, WI, QMP and DMP and check to see if there is a change in clinical study site personnel.

Tuesday, November 3, 2009

CRF and DCF Tracking at the Clinical Study Level

The last several blogs pertained to the management of data, discrepancy, quality control, audits, etc., at the Clinical Study Level. This blog pertains to the careful management and tracking of CRFs and DCFs at the Clinical Study Level.

To document data management clinical study progress, while following DM SOPs and WIs, the selected CRO(s) must be required by the sponsor pharma to provide regular metrics reports for CRF and DCF Tracking. The frequency and timing of these reports must be determined on a per study basis.

At a minimum, the following metrics must be tracked for CRFs:
  • Complete CRFs received (all expected visits for the subject received)
  • Total number visits received
  • Total number visits entered
  • Total number reviewed
At a minimum, the following metrics must be tracked for DCFs:
  • Total number generated/sent
  • Total number returned
  • Total number resolved
  • Number of DCFs outstanding greater that "x" days.
A mistake often made: The tracking tool used should not be a excel spreadsheet, spreadsheets can be changed by error, inadvertently and unintentionally by clinical study personnel. These spreadsheets are convenient to use but are not protected from erroneous revision and do not serve as GCP, Good Clinical Practice, accepted "source" documentation.

On scheduled, announced or unannounced "for cause" clinical audits, the use of excel spreadsheets for CRF and DCF tracking purposes will lead to a "failed" audit with serious regulatory, clinical and investigational repercussions.

Tracking records should be collected and versioned in an agreed upon "safe, lock-out" template, final version saved to an archive at the Clinical Study Site, the CRO, at the sponsor pharma, usually placed in the DM folder on the computer hard drive with paper copies to file in the DM department. All agreed upon metrics and tracking tools must be documented in the Sponsor Pharma DMP - the Data Management Plan.

Monday, November 2, 2009

Managing Data Changes - Clinical Study Level

The sponsor pharma selected a CRO to monitor and process the clinical study data and database. The CRO now must maintain an audit trail to document any data changes that occur after data entry in the clinical study database. What should the data audit trail contain? At the very least the data audit trail should contain:
  • sponsor pharma name/protocol number
  • investigator number
  • patient number
  • dataset name
  • CRF page
  • variable name
  • old value
  • new value
  • date/timestamp of change
  • person who made change
  • reason for change.
There are generally two types of data changes. Data changes arising from DCFs generated by a CRO monitor, CRA, CRC, DM, QC, QA or quality control process and "obvious errors". Be careful making data changes pertaining to "obvious errors". Be careful of "obvious errors".

Obvious errors are corrections that result in data changes that can be made "without" a confirmatory DCF issued. These corrections are self-evident based on the review of corresponding CRF data. There must be Generic Guidelines as well for Handling Obvious Errors and most importantly, the sponsor pharma is the only authority that can approve Obvious Error corrections, not the clinical personnel at the site, not the investigator. Final approval is only made by the sponsor pharma which is ultimately responsible for the integrity of the final clinical study data and clinical study database.

Monitor the monitor, monitor the data, monitor changes to the data, monitor the audit trail - as a sponsor take an active role in the quality control of the data and database at the clinical study level.

Sunday, November 1, 2009

Data Management CRO/Sponsor Pharma Roles

The role of the data management CRO chosen by the sponsor pharma to conduct clinical studies at designated and approved sites, domestic and international, and leading to an integrated clinical submission, CTD, eCTD, Clinical Phases 1,2,3, are as follows:

  • Tracks receipt of all data
  • Enters data into the database (at the clinical study level)
  • Performs data review through execution of programmed edit checks as well as through a manual review of the data
  • Maintains an audit trail of all database changes
  • Provides adverse event and concomitant medication coding listings for review
  • Maintains documentation of the resolution of all discrepancies, including those that did not result in a DCF
  • Manages the receipt, loading and processing of any external electronic data received for the clinical study.
  1. Interview the CRO.
  2. Investigate where the CRO conducts studies, North America, South America, Europe, other.
  3. Investigate the experience of the CRO, what indications, which therapeutic areas, safety, efficacy, BE/BA, Clinical Phases 1,2,3, oncology, neuroscience, respiratory, drug, device, biologic, other.
  4. Examine the correspondence and communication tactic of the CRO with FDA.
  5. How well recognized and respected is the CRO in the eyes of FDA?
  6. Ask for a "track record" of approvals, RTFs, filings, Clinical Submissions, eCTD, CTDs globally.
  7. Look at the credibility and experience, resumes and CVs of the CRO staff.
  8. Ask for the resource and capacity available for your clinical studies - some CROs are "over-booked".
  9. Ask for the client list of the CRO.
  10. "Interview the CRO" before making a decision.
  11. Once the CRO is chosen, develop quality management plans to monitor the CRO, contract, conduct, performance, data, etc.
  12. "Monitor the Monitors".
  13. The ultimate responsibility of a credible clinical study and a database with data integrity and accuracy is the sponsor pharma.
  14. Perform Quality Control and Audits periodically during the course of the clinical study.
  15. Start early, after several patients are eligible and enrolled in the clinical study, quality check the data and documentation and paper trail at randomly selected sites.
  16. Use Quality Data Management and Quality Control SOPs and WIs for checking selected clinical study sites.
  17. Monitor the Monitors!

Thursday, October 29, 2009

Quality Data Management at Clinical Study Sites

At a clinical study site, who is responsible for quality controlled data, data review and data discrepancy management? Well, the immediate answer is everyone. The responsibility for accurate data lies with a team, each team member responsible for a specific task.
The team members are:
  • Data Manager
  • Quality Data Controller (most often this task is outsourced to consultants)
  • Medical Monitor
  • Data Management Clinical Research Organization (CRO).

The impact of data discrepancy is pervasive, time consuming, laborious and far reaching. Procedural tasks and steps involved in quality data control and review at clinical study sites include:

  • Data Receipt and Entry
  • Data Review
  • Data Quality Control
  • Data Changes
  • Medical Coding
  • Electronic External Vendor Data
  • CRF and DCF Tracking
  • Quality Management
  • SOPs, WIs for Discrepancy Management and Tracking.

It is important to see into the future with respect to accurate data and clinical study databases. At the end of Clinical Phase 2 or beginning Phase 3 Clinical Studies, companies begin to consult with regulatory and clinical submission consultants or companies to create and develop the GIDB - "global integrated database". As a requirement, two GIDBs are developed, one for safety, Phases 1,2,3 and one for efficacy, Phases 2,3. The two GIDBs are developed from the pooling of all required clinical study databases performed during the clinical development and clinical submission time of the drug prior to filing. One discrepant datapoint will impact the data accuracy of thousands of globally integrated SAS programmed statistical tables, listings, graphs and figures. Finding that one discrepant datapoint is like finding a needle in the haystack - not a pretty job, costly and very time consuming, often impacting writing and filing timelines.

How to avoid?

Agree and adhere to process and procedures to ensure quality, accurate data at the clinical study level. Don't wait to find data discrepancies in the GIDB. Use quality data management early in the clinical development and clinical submission plan(s). Avoid data integrity issues early at the clinical study level.

Tuesday, October 27, 2009

Quality Control of Data, Data Review and Discrepancy Management

Standard operating procedures (SOPs) and Work Instructions (WIs) pertaining to data review and discrepancy management are created and used by pharma to ensure that data recorded at the clinical study site is adequately tracked, entered and reviewed within the clinical study database. This data should be systemically and periodically checked for accuracy, consistency and completeness as well as ensuring that errors are investigated and resolved. Another term used to describe data review and discrepancy management procedures are SOPs and WIs outlining "quality control of data".

Quality control of data, data review and discrepancy management will also ensure that documentation exists at the clinical study site.

Quality control of data, data review and discrepancy management ensures that all data discrepancies between the Patient Case Report Form (CRF) and the clinical study database are investigated and resolved.

The SOPs and WIs created and used in pharma for quality control of data, data review and discrepancy management should also include an outline defining metrics for tracking progress, status and quality of the clinical study database.

SOPs and WIs, must include the following parameters:
  • purpose
  • responsibilities
  • procedures
  • documentation
  • edit checks
  • guidelines for handling errors
  • error listings
  • history of data revisions
  • cover memos to cover receipt of error listings
  • metrics
  • tracking
  • and much more.
It is advised that SOPs and WIs themselves be reviewed and agreed upon by the pharma team responsible for the clinical study before one patient data point is collected at a clinical study site and entered into the clinical study database.

Monday, October 26, 2009

Stability/Clinical Studies - 505(b)(2) - Rate-Limiting

Just moments ago, a pharma company called and asked "Are stability and/or clinical studies the rate limiting factor(s) pertaining to FDA clinical submissions using the 505(b)(2) process"?

My advice to the pharma company was as follows and I would like to share this information in this timely post.

All too often, stability studies are the rate-limiting step in the timelines and flow pertaining to ongoing activities of a clinical submission.

The clinical program for many 505(b)(2) drug development programs is often ahead of the formulation development, analytical methods development and up-scale activities. For this reason, some pharma sponsors of the clinical drug submission accept the risk and scale up early in Clinical Phase 1 Study.

However, while in Clinical Phase 1, to mitigate risk, prudent comparability protocols must be included which can answer a lot of questions and help to minimize risk.

Sunday, October 25, 2009

505(b)(2) CMC Role in Clinical Submission

Since the 505(b)(2) clinical submission process is still in its ~first decade with FDA, a question often asked by pharma is "How does CMC (chemistry, manufacturing and controls) play a role in the clinical development program for a 505(b)(2) clinical submission"?

During the 505(b)(2) drug clinical development process, pharma often will change the formulation, components or API (Active Pharmaceutical Ingredient). The impact of any of these changes must be evaluated for impact on the safety, efficacy and tolerance of the proposed drug product. A review of the evolution of the formulation and the data supporting the comparability of the different formulation(s) form the basis for the "Pharmaceutical Development" section of the CTD ( Common Technical Document) clinical submission. A CMC "bridging" study can accomplish these goals.

All sections of the CTD are important, however, CMC is one of the most important and the data must be quality controlled from formulation to formulation, lot to lot, batch to batch, change to change. CMC is the foundation of the drug product.

  • a review of the implications of changes during the clinical development process
  • incorporate comparability protocols at the right point in the program
  • provide a coherent and approvable pharmaceutical clinical development summary for the proposed drug product.

Friday, October 23, 2009

505(b)(2), Importance of a Bridging Study

Since the 505(b)(2) process is relatively new to pharma and in fact, is still evolving at the FDA, one component of the regulatory clinical submission is a must in this process and that is a bridging study.

Pharma often ask, what is a bridging study and why is it pivotal as it pertains to the 505(b)(2) regulatory clinical submission process?

A bridging study, is a Phase 1 study and is used to compare the systemic levels of the drug(s) between the proposed drug product and the reference product. If properly performed and completed, a bridging study allows a pharma company to reference the safety, efficacy and tolerance data that is already known from the original regulatory clinical submission.

In fact, the key pivotal difference between a 505(b)(1) or a 505(b)(2) regulatory clinical submission is exactly the "bridging study".

Always remember, whatever regulatory clinical process used, data integrity and quality controlled data is essential. Therefore, when using the 505(b)(1) or 505(b)(2) regulatory clinical submission process, all data must be quality controlled, concise, accurate, statistically and clinically significant and must be consistent with previously submitted data to regulatory authorities worldwide.

To achieve and ensure quality clinical data, pharma must invest time and a budget to enlist a team of highly experienced clinical data controllers and data managers, "data gate-keepers".

The time and costs involved are minimal when considering and understanding the advantages of data that is quality controlled and pristine. As a result of data integrity, pharma will not have to engage in long question and answer periods pre-filing or post-filing, curious lack of data integrity, under reporting of adverse events and otherwise. The otherwise can lead to regulatory clinical submission and clinical study holds, a RTF and regulatory action letter(s) that are unfavorable to the drug, the data, the pharma and the overall approval.

Remember, always quality control your data.

More About Understanding 505(b)(2)

A question often arises with pharma and that is...Is the 505(b)(2) process and approach equivalent to the drug repositioning process and approach?

The answer is no. These are two different regulatory approaches and processes to leading to drug applications and approvals.

No, the drug repositioning process is where pharma takes drugs that failed clinical programs and make changes in the endpoints of their studies or make changes to the molecule itself in order to get approval.

This is clearly different that the 505(b)(2) process.

Don't be confused - it could result in a RTF or worse - actions that could be taken by FDA.

Thursday, October 22, 2009

Understanding 505(b)(2) and Why

Let us consider for a moment the 505(b)(2) regulatory approval pathway, why you should use it and how it differs from 505(b)(1). What are these two entities? Both are regulatory pathways pertaining to a new drug application (NDA).

The 505(b)(1) process is what the industry is familiar with - this process is used by pharma for new drugs that are new discoveries, new chemical and biologic entities.
The 505(b)(2) process takes drugs that have already been approved and makes small modifications to them often allowed by FDA for significantly advancing patient safety and benefit.
Now, more than ever, the 505(b)(2) process should be used by pharma in times of economic stress and when we are faced with reduced budgets, reduced R&D and shorten timelines.

* The 505(b)(2) process is relatively low risk because the drug has already been proven to be safe.
* It is low cost because there are fewer studies.
* It is also faster due to fewer studies, and if done right, a drug can make it to market in as little as 3 years.

In the economic and competitive climate of today, I strongly suggest that pharma consider the 505(b)(2) process for getting drugs approved and to the market.

Thursday, January 22, 2009

Quality Control {QC} of NDA/eCTD Submission Documents

From the desk of Dante.

  • The submission is complete.
  • The regulatory forms filled out.
  • The checklist is being filled in.
  • Timelines are met.
  • While reviewing some late data, you find an error.
  • Panic begins.
  • QC was never performed or even part of the submission plan.
  • What happens next is a horror.

  • QC of submission data and documents is important.
  • QC can vary significantly from company to company.
  • QC and the process and planning should begin at the very beginning with the programming of data, the writing of clinical study reports and as the eCTD pyramid builds into integrated databases, clinical and nonclinical summaries and high level overviews.

It is a daunting task, but a solid QC plan is a must to ensure low error rates and data accuracy and consistency.

Friday, January 16, 2009

GIDB - Global Integrated DataBase

From the desk of Dante.

Early in the planning stage of your GIDB and SAP {Statistical Analysis Plan} remember for clinical safety data, FDA is asking pharmaceutical companies to integrate their data in this manner:

  • Phase 2-3 database - dose-finding and pivotal studies
  • Phase 1 database - "some pooling across all studies".

Also, an ISS {Integrated Safety Summary} is often required, even though the eCTD submission backbone assigns safety data to Module 2.7.4, the Clinical Summary of Safety.

I strongly advise an open communication and negotiation with FDA concerning data presentation and integration in your submission, however, in my experience, the above rule almost always applies with global safety data.

Friday, January 9, 2009

21Part CFR FDA Guidelines "are" Critical Path Tools

From the Desk of Dante.

How important are "Critical Path Tools", commonly know as FDA Guidelines? Extremely important. Yes, you are correct, guidelines are not "requirements", however, in many cases, will have greater impact on the overall success of the drug's development phase and ultimate chance for approval.

FDA Critical Path Tools {Guidelines}:
  • are science-based documents that eliminate uncertainly and ensure quality and integrity
  • will provide valid evidence of product safety and efficacy
  • will provide manufacturing quality and consistency.

I encourage all stakeholders to:

  • collaborate
  • improve
  • negotiate
  • and communicate...with FDA on guidelines, and of course, follow the requirements.

Start today!

Tuesday, January 6, 2009

When do you think Quality Control begins...

...Patient Case Report Form {CRF}?
...Investigator's Brochure {IB}?
...Study Database Lock?
...Patient Profiles?
...Expedited Safety Reports?
...CRA Monitoring Reports?
...SAS Data Tables, Listings, Graphs and Figures?
...Statistical Analysis Plan {SAP}?
...General Investigational Plan {GIP}?
...Investigational New Drug Application {INDa}?
...In-license of a potential new drug or company acquisition?