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.