FDA & EMA Regulatory Developments for eSubmissions

May 14, 2012

eSubmissions

Regulatory Developments for eSubmissions

A few months ago, GxP Perspectives discussed eCTD as a Required Format for FDA Submissions. To summarize, in PDUFA V Commitment Letter 8-31-2011, the agency announced their intention of issuing draft guidance for required electronic submissions in eCTD format by December 31, 2012, with final guidance no more than 12 months after the close of the public comment period. Twenty-four months after publication of the final guidance, electronic submissions will be required for all new NDA and BLA submissions (originals, supplements and amendments) with a few specified exceptions. In this update, Kathie Clark discusses upcoming requirements, developments, and incentives for sponsors of clinical research.

Recent eSubmission-Related Regulatory Developments and the Impact on Sponsors
by Kathleen Clark

The regulatory authorities have been busy announcing plans and issuing new guidance related to eSubmissions in recent months. Legislation has been proposed to expedite review of generic drug applications and improve communication between FDA and industry – Generic Drug User Fee Act Program (GDUFA). GDUFA includes goals for FDA such as reviewing and acting on 90% of complete ANDAs within 10 months after the date of submission – but these goals only apply to submissions made electronically, following the eCTD format.

New Initiatives in Europe

regulatory developments for eSubmissions

New Developments in Europe

In Europe, the big news has been the eXtended EudraVigilance Medicinal Product Report Message (XEVPRM). XEVPRM is an XML-based message format that defines the structure and data elements required to unambiguously identify a medicinal product. European Medicines Agency requires that by July 2, 2012, information on medicinal products for human use authorized or registered in the Union is submitted electronically in this format. Sponsors are scrambling to meet this mandate as guidance has been finalized only recently.

Sponsors are often challenged to locate the data needed for submission, and ensure that it is complete and accurate. Vendors have been following the initiative closely, but even so, deploying and validating systems to publish the new message and putting in place the business processes around their use is a significant effort. Some aspects of the mandate remain unclear.

Another ongoing initiative in Europe is the pilot program for the new electronic Application Form, or eAF. The eAF is actually a collection of electronic Application Forms for human and vet med MAAs as well as variations and renewals. These are PDF fillable forms requiring extensive, detailed information for completion. Use of the electronic application forms is expected to yield the following benefits:

• Improvements to data quality and consistency during data entry

• Access to the underlying data entered into the forms in an XML format

• Integration with dynamic lists of controlled terminologies

The eAF pilot commenced on March 12th 2012 and is expected to run for four months.

FDA’s New Validation Criteria and Module 1

The FDA has finalized new eCTD Validation Criteria. They have not yet announced an implementation date, which will be set at least one month in advance of enforcement. The validation criteria represent a major overhaul:

• 56 new validation checks (5 high, 36 medium, 15 low) – 12 checks will be removed

• 161 unique error conditions – of which 22 errors can cause a technical rejection
In the past, the FDA has not validated the actual PDFs that make up the majority of an eCTD submission. The new criteria require extensive validation of the PDF files themselves. This includes validation of

• Fonts (use of standard fonts embedded where required)

• PDF format (1.4 or 1.7)

• Absence of applied security (either password protection or restrictions such as preventing the selection of text)

• Generation of PDFs in a manner that allows them to be text selectable (from electronic sources as opposed to scanned)

regulatory Developments for eSubmissions

FDA’s New eCTD Validation Criteria

The FDA will also be validating bookmarks and hyperlinks to ensure that they are valid and don’t point to external or non-relative locations. Finally, the FDA has provided rules to help sponsors correctly name and place their PDF fillable forms. This is essential as the FDA reads data from these forms that allows submissions to be processed by their automated software, without manual intervention. This is also important to sponsors, as failing to supply valid forms can result in up to five days delay in processing a sequence.

A fillable form should always be submitted, and should be named properly. As FDA requires forms to be signed, if sponsors have trouble applying digital signatures, they should still fill out a PDF form, print, sign, scan, and submit both forms. For details, see the FDA presentation CDER Update: eCTD & Gateway Submissions.

FDA’s Draft Module 1 Guidance

The FDA plans major changes for Module 1, and have issued new draft US Module 1 and Comprehensive Table of Contents Headings and Hierarchy Guidance. These guidances are still subject to change and not likely to be implemented until early 2013. The changes include:

• Allowing for bundled submissions (one sequence submitted to multiple applications). Examples of bundled submissions include new manufacturing site, change in API source, a drug substance change that applies to multiple dosage forms of the same drug, changes in packaging, etc.

• Ability for attribute display values to be updated without having to update the Specifications, eCTD TOC, and DTD .

• Revision of heading elements.

• Addition of new headings and sub-headings, including detailed definition under m1.15 Promotional material. These additions are too numerous to mention but are summarized in Appendix 2 of the comprehensive Table of Contents. (The FDA has emphasized that promotional materials are still not accepted in eCTD format at this time.)

• Addition of new attributes in Module 1 (under m1-forms and m1-15-promotional-material).

• Additions and changes to Module 1 metadata. These are too numerous to mention but are summarized in Appendix 2 of The eCTD Backbone Files Specification for Module 1.

Finally, the FDA has updated the way it organizes regulatory activities within an application. (A regulatory activity is a set of sequences that together constitute a claim, e.g. an original application, supplement or annual report). There are three levels of organization:

Application (e.g., NDA, BLA, IND)

Submission Type (e.g. Original Application, Efficacy Supplement, Safety Reports)

Submission Sub-Type (e.g. Application , Amendment, Resubmission)

Valid Submission types will be based on the Application Type, e.g., an efficacy supplement can be associated with an NDA or BLA but not an IND. The FDA provided a figure to illustrate how the approach works in comparison with the previous approach.

You can see a number of FDA presentations on the topic of Module on the Electronic Submissions Presentations page.

Health Canada Updates

Health Canada is also planning extensive changes. They have issued new draft guidance for CTD, eCTD and Module 1. Health Canada is formalizing the concept of Regulatory Activities through use of the related-sequence metadata. Their regulatory activities are defined in their Module 1 guidance and include New Drug Submission, Supplement to a New Drug Submission, Abbreviated New Drug Submission, Clinical Trial Application and many more. Clinical Trial Applications are not yet being accepted in eCTD format but that is expected to start around the end of 2012.

There are many changes to the table of contents, including correspondence organized under 1.0, much more granularity around 1.2 Administrative Information, more headings under Product Information (IB, more labeling elements, PV/Risk Management plans and information), change of 1.6 Electronic Review Documents into Regional Clinical Information, a new section 1.7 for CTA information, and a new regional quality section, 2.2.R.4 Yearly Biologic Product Report.

eSubmissions regulatory updateHealth Canada is also making major changes in its Module 1 metadata, including adding elements applicant, product-name, dossier-identifier, dossier-type, regulatory-activity-type, regulatory-activity-lead and removing elements submission-identifier, and submission-date.

Finally, on the technical front, the eCTD guidance calls for a technical change to the use of a Schema instead of DTD.

What Can Sponsors Do to Prepare?

Although some of these changes are only in draft or pilot stages, preparation should begin now. Suggested preparation steps include:

• Review the guidance documents and agency presentations

o Ask questions – esub@fda.hhs.gov is a great resource for FDA issues if you need clarification

• Understand the new documents required in the CA/US M1

o Do they already exist and are just not submitted? Or must they be created? Under which circumstances?

o Are they being created using high quality templates authored to the correct granularity?

o How will you handle promotional materials with non-traditional formats (movies, artwork, etc.)?

• Review the new validation criteria

o Are PDFs being created in a compliant manner?

o Are US Fillable Forms being created and published correctly?

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EudraVigilance Medical Product Dictionary

FDA Electronic Submissions Page

Kathie Clark is Director, Product Management for NextDocs, a leading provider of SharePoint based content and quality management systems for Life Sciences. Kathie has an extensive background in document management and electronic submissions for the global life sciences industry and has written extensively about industry challenges in blog posting, journal articles and white papers. You can reach her at kclark@nextdocs.com or follow her on twitter at @kathie_clark.
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Also this marks three years for the great blog by Steven Grossman, FDA Matters. Congratulations Steven! You can read his post on FDA, Me, and Maybe the Mafia!


FDA IP Labeling Requirements

April 29, 2012

FDA labeling investigational product

Does FDA Require an Expiration Date for IP?

What are FDA’s requirements for labeling investigational drug and biological products (IP)? We are all aware of the required statement in 21 CFR 312.6, “(a) The immediate package of an investigational new drug intended for human use shall bear a label with the statement ‘Caution: New Drug–Limited by Federal (or United States) law to investigational use.'” However, is that the only requirement? What else, if anything, belongs? What labeling is against FDA requirements? Is this a GCP or GMP issue? This question came up recently in a discussion with a colleague. It was their opinion that an expiry date was not required. They had stability records for the IP and could show that the expiration date exceeded the length of the trial. Is this sufficient? I disagreed. I felt that the IP labeling should include a lot/batch number and the expiry date.

What Are YOUR Viewpoints? Please comment below.

FDA regulations for investigational new drugs tell us little about what goes on to an IP label. However, we know that IP must be manufactured under the GMPs. Just what do the GMP regulations say about labels? We can find it in § 211.137, Expiration Dating. It states in 211.137(g):

“(g) New drug products for investigational use are exempt from the requirements of this section, provided that they meet appropriate standards or specifications as demonstrated by stability studies during their use in clinical investigations. Where new drug products for investigational use are to be reconstituted at the time of dispensing, their labeling shall bear expiration information for the reconstituted drug product.”

FDA Drug Labels

Consultant's Don't Enjoy Being Wrong

It is clear that my colleague is correct. FDA does not require expiration dates if the IP meets the standards and/or specifications in stability studies. I don’t like making mistakes, but “the proof is in the pudding.” This is a very specific regulation that is easy for all of us to interpret. I would have appreciated it if FDA had referenced this in the IND regulation, §312. That is where most GCP professionals go to look for FDA’s GCP requirements. However, FDA frequently doesn’t appreciate what I appreciate, so we find the information in §211.

The second point that this regulation makes is very interesting. More and more drug products require very specific instructions on how to administer the drug or IP. A reconstituted test article can have a very short time period for dispensing. This regulation is equally clear that “their labeling shall bear expiration information for the reconstituted drug product.”

This can add up to a lot of information. Expiration information for a reconstituted drug product, storage temperatures and conditions, and adequate directions for dispensing the IP are all essential information for a label. How in the world do you fit it on one small container? For this, you need to understand FDA’s definition of “label.”

In conducting your clinical research program your ultimate goal is to attain a “label.” This is the physician’s insert that informs the clinician, among many other things, “adequate instructions for use.” Vials of parenterals are usually packaged and the packaging contains essential information that is also considered labeling.

FDA investigational product labeling

FDA Labels Must Not be Misleading

In addition, the handy “informational sheets” that some nutritional supplement or “neutraceutical” dealers keep under the counter at their stores and are given out to answer question from consumers also meet FDA’s definition of labeling. So when they hand you an informational brochure saying that “many studies find” that patchouli oil cures arthritis, yes that can be part of the label. Chances are that FDA would probably find it to be false and misleading.

That means you should have plenty of room for this information on the IP labeling. Referencing it on protocol-specific worksheets that the clinical site may, or may not, use for recording source data is not sufficient. The information needs to be part of the labeling or clearly stated in the protocol. It can also be part of pharmacy manual that is referenced in the protocol. The information needs to be readily available and part of the pre-study training that the sponsor documents before enrollment of subjects.

FDA Labeling

European Requirements

Finally, a European employee of the company my colleague works at informed me that it is an EMA requirement to include the expiry date. However, she had heard that in the U.S. there was no requirement, which she found strange. I find it strange as well. It is my viewpoint that in an era of globalized trials, we should aim for the highest standard. And harmonizing label requirements, when possible, will help the company develop a systematic approach to GCP compliance.

My personal opinion is that expiration dating is essential information for “adequate directions for use,” as required by Section 502 of the FD&C Act. I agree with EMA that the expiry date should be part of the label. However, I live in Tacoma, WA, not in Paris, Copenhagen, or Venice. So my personal opinion is just that, my personal opinion.

Carl Anderson, GxP Perspectives

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Please join your industry colleagues in completing the 2012 TMF Reference Model Survey, and use results to inform your TMF best practices.

https://www.surveymonkey.com/s/FPP8DCF

This fifteen minute survey is designed by members of the TMF Reference Model team to provide valuable insight into Trial Master File practices, both paper and electronic, to identify common problem areas, assess changes in practice and reveal opportunities for improvement. All respondents who complete the survey and provide contact information will be provided with the survey results.

Data collection closes June 1st; please join us today.

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What is Your viewpoint on IP labeling? Please comment and let us know.


TMF Reference Model Update

March 18, 2012

TMF RM

The Trial Master File (TMF)

The recommended and required contents of the TMF, the trial master file, continue to be a concern for clinical trial professionals. This blog continues to support the efforts of the DIA working group for the TMF Reference Model, originally issued in 2010. The most recent updates to the TMF RM within Version 1.2, which was released in December 2011, featuring TMF components at the clinical sites along with those kept by the sponsor. The next version of the TMF RM is planned for release in June 2012. There is expected to be some updated content as a result of feedback received from broad industry use of the model, in addition to extension arms of the model for device and investigator-initiated trials. In this Guest Commentary, Lisa Mulcahy, co-chair for the TMF RM working group, explains the basics of the TMF RM.

The Trial Master File Reference Model

The Trial Master File (TMF) Reference Model (RM) is a supported initiative through the Document and Records Management SIAC of the Drug Information Association (DIA), a recognized and highly respected professional association. Creation of the TMF Reference Model has involved more than 230 representatives, all DIA members, from more than 150 bio-pharmaceutical companies, contract research organizations (CROs), consultancies, technical vendors, industry groups, healthcare, academia, non-for-profit / NGO and regulatory agencies. The attention of participants is drawn to the non-commercial nature of this forum. Although it is acknowledged that the resulting reference model ultimately needs to integrate with commercially available products, this was by no means a forum for promotion of products and companies.

The TMF RM was first released in June of 2010 and is a reference for the biopharmaceutical research industry. The model clearly outlines the content and organization of TMF content, at both Sponsor and Investigator site. TMF RM is a reference for the industry and should not be considered mandatory, but rather as an opportunity for standardization across the industry. The TMF RM can be adapted to an electronic or a paper TMF and does not endorse, nor by design, require, any specific technology for application.

The goal of the TMF RM is to provide a single, unified interpretation of the regulations via document listing which would be accepted across the industry. It does not provide guidance in the process by which the document is the output.

Use of the model

The uptake of the TMF RM is broad and it is at a minimum being used as a tool to compare against sponsor already-defined TMF content. It is most often though being adapted or adopted by companies as it provides a comprehensive listing of content created in support of a clinical trial.

Rationale for the creation of a model

The TMF contains those essential documents that individually and collectively permit the evaluation of the conduct of a trial and the quality of the data produced. These documents serve to demonstrate the compliance of the investigator, sponsor, and monitor with the standards of GCP and with all applicable regulatory requirements (ICH Guideline for Good Clinical Practice, E6, Section 8).

TMF Reference Model

ICH E6

Regulatory guidance, such as ICH E6 section 8, addresses only a sub-set of TMF documents. Documentation requirements for the set-up and maintenance of quality systems, electronic systems, safety monitoring, and proof of an adequate and well-controlled trial, to name a few, exist in various regulations across many countries or regions, but not in ICH E6.

The following are additional reasons for creation of the TMF RM

• All companies and investigators conducting clinical trials in the pharmaceutical/biotech industry maintain documentation for each clinical trial. Each company has their own unique TMF structure as defined by their SOPs. No comprehensive common model exists for managing TMF documents. Over the conduct of a trial many functions contribute to the TMF, although oversight of the content is usually not one function’s responsibility – resulting in a highly inefficient work processes including but not limited to:

• All drug development companies and CROs expend considerable resources defining the content of the trial master file for each clinical trial. Consequently, Investigators have the challenge of adapting to different formats and TMF content organization with each clinical trial.

• The burden is very high on smaller companies that usually have limited document management expertise and limited financial resources.

• Records and information exchange between collaborating companies is extremely cumbersome, potentially preventing the joint venture or transfer of an investigational product.

• Regulators are challenged with varying terminology and file structures, creating inefficiency and variability during audits
Organization of the model

TMF

TMF Artifacts

Defined in the model are document types, called artifacts, which one would expect to find in a TMF, at both Sponsor and Investigator site. The artifacts are labeled either core, meaning it must be in the TMF as dictated by either the ICH Guidelines, regulations, or the TMF RM group (if applicable for the trial), or recommended meaning the artifact does not have to be produced but if it is created or collected, it is recommended to be in the TMF. Since the industry often uses unique names, alternate names (as relevant) and descriptions are supplied for each artifact. If the artifact is referenced in the ICH Guidelines, this information is captured.

The artifacts have been organized by Zone – where like artifacts are grouped together:

• Zone 1 Trial Management
• Zone 2 Central Trial Documents
• Zone 3 Regulatory
• Zone 4 IRB/IEC and Other Approvals
• Zone 5 Site Management
• Zone 6 Investigational Product (IP) and Trial Supplies
• Zone 7 Safety Reporting
• Zone 8 Centralized Testing
• Zone 9 Third Parties
• Zone 10 Data Management
• Zone 11 Statistics

Artifacts are created and can exist at multiple levels such as trial, country, and site. An artifact, such as “Safety Management Plan” exists at only 1 of the levels, the trial level. In contrast, the artifact “Informed Consent” can exist at all three levels. These levels can be used to define the paper format TMF.
The TMF RM can be found, free to the public using the following link (cut and paste into web browser address bar:

Metadata

The TMF reference model also details basic metadata which can be used as a starting point for building TMF electronic content management processes. This metadata model can be applicable in all electronic settings, from the straightforward file share to the complex enterprise system.

TMF Reference Model

"This model is designed to capture the unique set of documents"

The trial number is captured on each of the artifacts in the TMF RM. Since this model is designed to capture the unique set of documents associated with a single trial, the trial number is attached to each artifact. Inherited metadata such as Product/Compound, Indication, Trial Phase, and Route is also attached to each artifact and would be required to be entered only once, dependent upon system design.

Date format and convention for which date is captured on an artifact present on every artifact and has been left to those interpreting the reference model within already defined processes. Artifacts would have country metadata associated with them if they were to be created for a specific country and a site number/ID if created at the site level.

Lisa Mulcahy

The TMF RM Online

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Please join your industry colleagues in completing the 2012 TMF Reference Model Survey, and use results to inform your TMF best practices.

https://www.surveymonkey.com/s/FPP8DCF

This fifteen minute survey is designed by members of the TMF Reference Model team to provide valuable insight into Trial Master File practices, both paper and electronic, to identify common problem areas, assess changes in practice and reveal opportunities for improvement. All respondents who complete the survey and provide contact information will be provided with the survey results.

Data collection closes June 1st; please join us today.

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======== A GxP Perspectives Editorial ========

It came as a surprise that Wikipedia, under Electronic trial master file, has a subjective entry regarding the TMF RM. Regarding the TMF RM it states: “it fails to specify any electronic format for consistent document and record exchange.” It then goes on to suggest another group is doing a better job: “In an effort to resolve the obstacles around the electronic exchange, sharing and interoperability of electronic trial master files, http://www.etmf.org eTMF.Org was formed in 2011 to develop a standard for the secure exchange and sharing of eTMF archives…” This is an organization that lists four experts on its website. This is in contrast to over one hundred industry professionals, including myself, who have worked over the past few years on the TMF RM.

Wikipedia can be a useful research tool when the articles are objective and well researched. This article is currently rated 3.6 of a possible 5.0 for objectivity. You can read it for yourself, and rate it accordingly at the following link.

Wikipedia eTMF Article

GxP Perspectives welcomes all comments on the TMF and the efforts by the TMF RM working group and others on the best way to advance a coherent, usable TMF guidance.

Carl Anderson, GxP Perspectives

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FDA has issued the final guidance, “IRB Continuing Review after Clinical Investigation Approval.” GCP Guidance Documents may be found here: FDA GCP Website. The new guidance is on the right in the section “In The News.”


India: Quality for Clinical Trials

March 1, 2012

India clinical trials quality assurance

Quality Systems in India

Are Quality Systems in place in India, where the clinical trials industry is exploding?Do clinical trials professionals have the knowledge, skills and experience to run clinical trials where the rights, safety, & welfare of human subjects is protected and where data are reliable for submission to FDA and EMA> In this Guest Commentary QA professional Anusha Reddy demystifies the GCP process in India outlining her approach to quality in clinical trials.

This marks the first edition of GxP Perspectives as a monthly blog. It has been too much work for one person to keep up with a weekly schedule. I will be using the GxP Perspectives Linkedin Group to keep on top of current developments with FDA, as well as discussions by group members. Also, youcan subscribe to the blog on the button to your right on the sidebar.

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Improvising Quality in Clinical Trials

By Anusha Reddy

Over the last decade Clinical Trials in India have increased very rapidly in number. India has made a name for itself in the international pharmaceutical field as an ideal destination for worldwide companies to conduct clinical trials which is a test for both the government and the private sector to create a balance between ethics and trade The rise in the business brought sharp focus on the need to manage quality while conducting clinical trials.A need was, however, felt to develop our own Indian Guidelines to ensure uniform quality of clinical research throughout the country and to generate data for registration for new drugs before use in the Indian population. An Expert Committee set up by Central Drugs Standard Control Organisation (CDSCO) in consultation with clinical expert has formulated GCP guideline for generation of clinical data on drugs.

The Drug Controller General of India (DCGI) has introduced several guidelines and regulations, in an effort to maintain and ensure credibility, integrity, safety, well being and quality of clinical trials, some which includes guidelines on approval of clinical trials, CTD, Clinical trial Inspection, registration of clinical trials, CROs, and Ethics Committee’s. It constituted NDAC to review applications of new drugs and clinical trials, introduced prescreening of applications in order to expedite and streamline the process of application by ensuring completeness and has recently made compensation mandatory for injury or deaths during trials and which would increase the number of volunteers and patients going for a trial in India, according to experts.
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quality clinical trials in India

"Each Stage of Data Handling"

Quality in clinical trials should be applied to “each stage of data handling” to ensure that all data are reliable and have been processed correctly. Clinical trials are carried out to allow safety and efficacy data to be collected to provide information for industry and regulators to make decisions about the safety and efficacy of the interventions. Activities like monitoring and auditing are performed in order to ensure that the quality exists and the study is conducted in accordance with the SOPs, Protocol, GCP and applicable regulatory requirements. Pharma and Biotech firms are looking for several different strategies in clinical trials to ensure the highest quality of data. This article tries to discuss on describing and executing the quality in clinical trials.

A good quality clinical trial should, address an important question, have the potential to make an actual difference to patients, use the finest available research techniques, generate significant data, be scientifically and ethically sound. Recognition of GCP at the sponsor, CRO and the investigator site will improve the quality of clinical trials and finally leads to the acceptance of clinical trials.

clinical trials quality India

"Ability to Satisfy Stated or Implied Needs."

As per ISO (International Organization for Standardization) quality is defined as the features and characteristics of a product or service that bear on its ability to satisfy stated or implied needs. In clinical trials, poor quality has much more serious outcomes than discontented customers. Failure to ensure quality in clinical trials can result in undue harm to research participants, invalid data, and consequently, wrong conclusions about the safety and efficacy of the drug being tested. Additionally poor quality is a call for a regulatory inspection.

Determined efforts to improve quality in clinical trials have increased noticeably over the past decade. Recently the Department of Medical Education has imposed a temporary ban on clinical drug trials and research projects in all government and private medical colleges and hospitals in the Karnataka State, India; however, later it was assured that no such measures are being undertaken. The reason behind such decision was especially lack of guidelines to regulate drug trials. An expert committee was set up to study and frame guidelines to regulate and re-organise clinical drug trials, which is a step towards a quality clinical trials.

quality India clinical trials

The Consequences of Poor Quality

There are several reasons for poor quality in clinical trials and preventing them all is not an easy task. The objective should be to limit their number and their effect on the trial outcomes. This can be achieved by taking steps at the initial stage in protocol development and at the trial set up phase to obtain a high quality data in clinical trials; however, this alone does not result in high quality. Furthermore, planning should be accompanied by adequate oversight through proper routine monitoring and auditing of the trials with necessary corrective and preventive actions (CAPA) in place.

Measures should be taken to promote quality improvement in clinical trials by following standard operating procedures and implementing good documentation practices while performing study activities like drug accountability, Informed consent process, Safety reports, protocol deviations/violations and other protocol related activities which will provide reliable results and error free data when submitted to regulatory agencies for approvals.

A quality system proposition to good clinical practice conformance will establish quality in clinical trials by identification and setup of standards, applying them by those involved in the conduct of clinical trial, tracking the areas that are non-complaint with the standard procedures or applicable regulatory requirements, take actions to prevent the recurrence in future in the identified areas.

quality in India

Developing Metrics

Developing and using metrics that are meaningful within an organization facilitate in measuring the quality in clinical trials. For example, preparing a protocol from the stage of drafting to finalizing, here with increase in amendments the time increases and quality is reduced (but number of amendments is often not the reflection of protocol quality). Other example for measuring the quality includes the number of data clarifications forms (DCFs) raised per case report form (CRF); increase in the number of data queries indicates the poor data quality. Based on these metrics one can measure the quality and can improve those areas.

In Conclusion, systems with procedures or measures that assure the quality of every aspect of the clinical trial should be implemented. Quality should be applied to each stage of data handling to ensure that all data are reliable and have been processed correctly. This extent of transparency and accountability of clinical trial processes ensures ongoing quality control and quality assurance, but in addition, makes it easy to assertively address inquiries from regulatory agencies.

Useful Links:

Indian GCP

Clinical Trial Registration

Prescreening Checklist

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Training Opportunity:

The 3rd Proactive GCP Compliance Conference taking place April 2-4 in Arlington, VA – GCP Conference Website. Leading GCP experts from Lilly, Pfizer, J&J, Novartis, Shire and many more address risk-based approaches to clinical quality that meet requirements and ensure patient safety. Special 15% discount off of the standard registration rate for GxP Perspectives readers. Register online at: GCP Conference and use discount code: P439GXP

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DIA Regulatory Conference this April in India

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In News From FDA:

FDA has issued the final guidance, “IRB Continuing Review after Clinical Investigation Approval.” GCP Guidance Documents may be found here: FDA GCP Website. The new guidance is on the right in the section “In The News.”

From: A Message from the Commissioner
Sent: Wednesday, February 29, 2012 04:14 PM
To: FDA-Wide
Subject: Announcement re Chief Counsel

Dear Colleagues,

I am thrilled to announce the permanent appointment of Elizabeth Dickinson as the Chief Counsel of the Food and Drug Administration, effective Monday, March 12, 2012.

As many of you know, Liz has had a long and distinguished history at the Agency; she joined the Office of the Chief Counsel in 1994. Over the years, Liz has served as legal counsel to the Center for Drug Evaluation and Research and the Office of the Commissioner on innovator and generic drug review issues, orphan drug development, and biosimilars; has implemented pediatric exclusivity and pediatric drug development programs; has worked closely with the Department of Justice on dozens of cases addressing Waxman-Hatch issues and preemption; and has coordinated the development of the Office of the Chief Counsel’s flexible workplace program.

A graduate of the University of Massachusetts and Northeastern University School of Law, Liz is highly regarded by both her internal colleagues and those across the food and drug bar. Over the years, Liz has received numerous awards for distinguished service, leadership and her outstanding legal skills.

Liz has been serving as Acting Chief Counsel since August 2011, and we have been grateful for her hard work and dedication each day that she has been on the job. It is terrific to know that she will be serving the Agency in this role permanently as we move forward. Please join me in congratulating Liz.

Sincerely,
Margaret A. Hamburg, M.D.
Commissioner of Food and Drugs

We have some excellent comments on this post. Please join the discussion and add your own thoughts


Drug Accountability in Clinical Trials

January 19, 2012

clinical trials study drugs

Drug Accountability in Clinical Trials

Drug Accountability Is the one thing that everyone looks at and everyone ignores in clinical trials. I don’t know how many times I have read in a monitor’s report that “drug accountability not done due to time restraints.” Yet consistently “test article accountability” (as FDA refers to it) is one of the top findings on a Form FDA 483, Inspectional Observations, issued for clinical trials. In this Guest Commentary pharmacist Roberta Wong outlines the basics for clinical trial professionals. She concludes with six issues for clinical trial sites to consider. She is a consultant to biopharmaceutical companies and teaches at the Pharmaceutical BioEngineering Program at the University of Washington.

Guest Commentary by Roberta Wong, PharmD

Drug Accountability in Clinical Trials

It’s not exciting, it’s not cutting edge. It may be the last thing you think about when preparing for an FDA audit. You might scan the records and figure if all the lines are filled in, it must be okay. Or, the auditor might not look at it, so I will trust that the pharmacist did it correctly. After all, aren’t pharmacists one of the most trusted professions? Consider this: if drug accountability is in question, then the whole study could be in jeopardy. Proving that the drug was administered to the patient that resulted in the effects seen from study drug is a key factor in determining the merit of a product candidate. The FDA has listed drug accountability as #3 in a list of top 5 pitfalls.

drug accountability in clinical trials

What FDA Considers

The FDA uses these categories for determining the seriousness of a deficiency. Sometimes, minor sloppiness is due to poor record keeping. This can be corrected with training, and close follow-up to insure consistency amongst staff. Sloppiness, if bad enough, can cause removal of data from study results, impacting the overall quality of the data, and the integrity of the study conduct. Often unintentional, lack of attention to detail, and not understanding the importance of accurate recordkeeping in the drug application can contribute to a clinical trial site’s data being thrown out of a sponsor’s application. Training staff at the study initiation visit and checking the quality of the work during the course of the study is critical for good record keeping to be maintained during the clinical trial. Staff can change, so retraining may be needed as new staff members are added to an ongoing study.

drug accountability in clinical trials

Intent to Deceive?

On the other hand, some inconsistencies in drug accountability can be due to a true intent to deceive. Drug supplies that are listed as destroyed, lost, or dropped, can be traced to individuals diverting supplies for themselves, or with the intent on selling study drug to other individuals. Investigational drugs can also be switched in an attempt to give drug preferentially to certain patients, if there is also a placebo as part of the study. Limiting access to investigational drugs is a key role for the pharmacist in studies conducted at large institutions. At smaller sites, or individual physician’s offices, study drug may be held by research or nursing staff. In these situations, limiting access and providing locked security for study drugs is required by the study sponsor.

So, what happens when a clinical trial site has drug accountability problems? If this occurs during a clinical trial, the Sponsor will stop new drug shipments, and may suspend study enrollment temporarily. Visits to the site by the sponsor will ascertain the cause of the problem, and determine if re-training will prevent future issues. During this investigation, reviewing the records with the study coordinator and the prinicipal investigator are imperative. And of course, documentation of any meetings with site staff summarizing the corrective action is essential. Ongoing audits for the remainder of the trial will demonstrate that the interventions were successful, and the site is now compliant in maintaining accurate drug accountability.

drug accountability in clinical trials

"Shooting the Dice" with Your Clinical Trial?

Drug accountability is more than just counting pills and vials. Site staff must insure that the study subject receives the study drug, and receives the correct dosage. There should be documentation to support drug administration. If the patient self-administers study drug, often diaries and pill vials are collected to validate the administration of study drug. If the drug is administered at a clinic visit, there are often forms to complete to verify the dosage that was given to a study subject.

How can you avoid problems with drug accountability? First, make sure that all involved in the study are consistent with their documentation. Make sure that the records are completed with the drug dose, patient, date, time and individual removing drug from the central inventory. If study drug is administered in the clinic, the worksheet should note the date, and actual time that the drug was given. If drug is not administered, even though a dose was prepared, then a note should record that drug was destroyed. If study drugs require refrigeration, then the accountability records should have a place to note the temperature.

Lastly, issues with accountability need to be addressed quickly and a solution determined. Vigilance in accurate documentation will insure minimal issues. Making sure the patient received the proper dose is one more way to insure that well-run clinical trials produce good quality data.

How do you know if your system is set up to produce good drug accountability? Here are some questions that you can answer about your study.

Questions to consider:

1. Did the patient receive the proper dose? How do you know?

2. Did the Physician calculate the correct dose? Who double checked the calculation? Is it weight-based? Is the dose calculated at study enrollment? Is the dose recalculated based on the patient’s baseline weight or dose the dose change only if the weight changes by 10%?

3. Drug was sent to the clinic to prepare a dose, and the patient was a no show. Should the drug be signed back into the central inventory? (If the drug should be refrigerated, and you are unsure of how the drug was stored, what should you do?)

4. Drug was prepared for a patient who was a no show, but promised to come in the next day. Can you save the prepared dose and administer it the next day?

5. Does your clinical trial allow documentation of these issues in the study records?

6. For study drug accountability, who resolves new issues? Where do you record your answer? How do you train the rest of the staff regarding this issue?

Contact Robbie!

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eCTD as a Required Format for FDA Submissions

October 29, 2011

eCTD Pyramid

The eCTD Pyramid

The electronic Common Technical Document (eCTD) is due to become a requirement in the immediate future (immediate in the FDA sense of the word). By 2017 FDA will have made the transition from paper to electronic submissions complete. Hopefully, the transition of most types of recordkeeping will also make the transition to electronic format. After the initial investment, this should cut the time and cost of bringing new health products to market. What do you need to know about eCTD? That’s the topic of Kathie Clark’s Guest Commentary.

Five Steps to Become eCTD Ready, by Kathie Clark

In FDA’s PDUFA V Commitment Letter 8-31-2011, the agency announced their intention of issuing draft guidance for required electronic submissions in eCTD format by December 31, 2012, with final guidance no more than 12 months after the close of the public comment period. Twenty-four months after publication of the final guidance, electronic submissions will be required for all new NDA and BLA submissions (originals, supplements and amendments) with a few specified exceptions.

Although many in industry were aware that the agency was preparing legislation to mandate eCTD, others have long been postponing moving to electronic submissions until FDA “pulled the trigger.” The good news is that FDA’s timeline still allows plenty of time for an orderly move to eCTD if plans are put in place now.

Here are some key steps to move to being eCTD-ready:

eCTD

Get Educated on eCTD

1. Get educated. If you are fortunate enough to have one or more team members with real experience in eCTD from a former employer, consider whether they can lead education and process transformation efforts needed to be eCTD-ready. However, be realistic about whether their day jobs allow for these activities. If you need help, consider sending employees for training – or better yet, bring in a knowledgeable consultant to educate your team and help them establish a plan for eCTD readiness. If you have more than a few employees who need training, it’s probably a more cost-effective approach, plus education can be tailored to the context of your submissions, taking into account what types of drugs or biologics you produce, whether generics are involved, which authorities you submit to, whether you will outsource or produce submissions in-house, and many other factors.

2. Understand and act on steps needed to make your source documents eCTD-ready. If you have been submitting paper eCTDs, you may not have been concerned about the quality or granularity of your PDF source documents. For more detail, see my recent article Five key steps for e-submission ready documents to avoid pre-submission rework on the Applied Clinical Trials website. It’s important to understand that you must produce submission-ready documents even if you plan to outsource submission preparation.

eCTD

The Decision to Outsource

3. Decide if you will publish submissions yourself or outsource to a partner. If you plan to outsource, you will need to develop a plan and questionnaire for selecting the most appropriate partner based on competence, cost, specific services offered, service level agreements, and other factors. If you will be publishing in-house, you will need to select, purchase and deploy a publishing tool and ensure that your employees are trained on it and have developed appropriate procedures. Don’t forget submission review – you may want to acquire the validation and review tools used by the agency or agencies you submit to.

4. Develop an overall timeline. Where do the above activities fall? What other factors, such as key submissions, influence the cut-over date that you plan?

5. Understand the logistics of the actual transition. The eCTD Summit blog entry Transitioning from Paper to eCTD at the eCTD Summit provides an excellent overview, with some good follow-up info from FDA correspondence found at the ask-cato blog. It’s best to treat this activity as a formal project, with a project manager, budget, schedule and milestones, and “definition of done” – what does eCTD-ready mean to you and how will you know when you have achieved it?

By planning now, you can achieve compliance in the specified timeframe while also moving to reap the benefits of implementing eCTD.

(eCTD pyramid graphic- Wikipedia)

By Kathie Clark

Kathie’s Website: NextDocs

Ask Cato Blog

The eCTD Summit

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Time is running out to comment on the Draft FDA Guidance on Risk-Based Monitoring!
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Guidance for Industry: Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring
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How to comment to FDA: Here is a two-slide powerpoint presentation on how to comment on the draft guidance document courtesy of CDRH BIMO. Thanks!

Location of Monitoring guidance FR

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clinical trials FDA monitoring guidanceThere have been some great comments on the GxP Perspectives LinkedIn group on the Draft FDA Risk-Based Monitoring guidance document and on protocol deviations. There is also a new logo for your viewing pleasure. I invite everyone to join the GxP Perspectives LinkedIn Group and join the discussion.

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On The Blogroll: Rebar Interactive (their twitter account is above) has an excellent blog. They are a digital media company with a focus on the clinical trials industry. Please check out their post on:
Patient Recruitment: Think That You Might Be Wrong,”
if for nothing else than the photo. A great blog post by Rahlyn.
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Please comment with your views on eCTD


An Ethical Question on Medical Oncology Research

October 25, 2011

oncology question

An Ethical Question on Clinical Trials

GxP Perspectives receives some excellent questions and comments about best practices. Here a regular reader asks a very pertinent question on Oncology Research. I don’t have the answer but I am hoping that the GxP Perspectives Community has some people that can help answer this for George. I hope so because I can learn a few things as well. Please comment if you have ideas for George and others to pursue.

An Ethical Question on Medical Oncology Research:

I am not sure the best place to post this question: I work in Medical Oncology Research and I have been noticing what I feel to be a distubing trend in manditory tumor tissue submission. In the past, studies required tissue samples if they were needed to determine eligibility or randomization to a treatment arm (Essentially something that was a potential benefit to the patient or needed to deterimne if study endpoints were met). Those studies usually gave patients the option to allow the sponsor to keep archived tissue for “future testing” that had no benefit to the patient or current study. Recently, some sponsors have been requiring this “archived tissue” as part of the inclusion / exclusion criteria – “If you don’t give us the tissue, you can’t go on our study.” Do you know if anyone is discussing this issue or is concerned how this may impact patient rights?

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Three Comments. The first is from Abby: If the intended use of the archival tissue sample is to send to a central reader to show that the subject indeed has the pathological diagnosis intended for the study, I believe this is a legitimate and important request by the researchers. In the case of a more nebulous use (e.g. “general exploratory pharmacodynamic studies” or “future use”), I do think it is good if the Sponsor can try to provide more specifics, such as “future use in cancer research” or something even better.

It has been my experience that the Informed Consent wording related to these samples must be very clear, and address the short-term and long-term storage of the samples, as well as information on how the subject may revoke that consent and have the samples returned. Clinical sites often request return of the archival samples on behalf of the subject, and sponsors often return the samples–especially if the subject is moving onto another study that also likely requires tissue. Interesting question–and I look forward to hearing other responses!

And the second is from Kevin: As far as the patient’s rights, they aren’t affected at all. As you state, it is clearly in the Inclusion criteria that if you want to participate, the Sponsor requires this sample. This should be included in the consent form as well. The patient, at this point, has the right say “no” to the study.

Sponsors routinely collect these samples as a way to further their research and hopefully capitalize on a novel therapy. I guess you can look at this in one of two ways: 1) Big Pharma is trying to make a dollar (…obviously, which is how/why they exist in the first place) or 2) since they have the ability to take the research beyond the confines of the current protocol, they may just find a cure or improved therapy, which in turn, benefits the patient.

It would be unethical only if the Sponsor took the sample and archived it without the patient’s consent.

My suggestion would to be to discuss your feelings with the Sponsor or to start with, perhaps your IRB.

And Eleanor: There is currently a significant shift in the approach to cancer treatment. In many cancers, there is not a universal response to treatment but some sub-populations respond much more effectively to treatment than the general population. In many cases this response to treatment relates to expression of certain genes by the tumour that do not occur in all patients with the disease. If it is possible to identify the gene and which patients express that gene then treatment is much more effective both in terms of success and in terms of cost.

This may be one of the reasons that sponsors are moving towards mandatory collection of samples. If they identify that a particular sub-population has responded more effectively they can go back and examine stored samples to try and identify the reasons that the sub-population responded more effectively. Thus, there may be the possibility of developing diagnostic tools to identify the sub-population and only treat that population. If there are only limited samples available then it may not be possible to do so. Just a thought…..

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Guidance for Industry: Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring
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How to comment to FDA: Here is a two-slide powerpoint presentation on how to comment on the draft guidance document courtesy of CDRH BIMO. Thanks!

Location of Monitoring guidance FR

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clinical trials FDA monitoring guidanceThere have been some great comments on the GxP Perspectives LinkedIn group on the Draft FDA Risk-Based Monitoring guidance document and on protocol deviations. There is also a new logo for your viewing pleasure. I invite everyone to join the GxP Perspectives LinkedIn Group and join the discussion.

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GxP Perspectives on twitter: @GxPPerspectives

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