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 To summarize, in PDUFA V Commitment Letter 8-31-2011, the agency announced their intention of issuing draft guidance for required electronic submissions in eCTD format by December 31, 2012, with final guidance no more than 12 months after the close of the public comment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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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.


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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ACRP Meets in Seattle for 2011 Global Conference

April 29, 2011

ACRP Seattle

ACRP Meets in Seattle for 2011 Global Conference

Seattle, WA plays host to the Association of Clinical Research Professionals’ (ACRP) annual Global Conference. ACRP is one of the larger professional organizations focusing on clinical trials and expects 2,000 participants. It will be the first time I have attended their Global Conference and I am looking forward to it. There will be sessions on “Introduction to Imaging in Clinical Trials” and on “Distance-Based Learning for Foreign Study Coordinators.” GxP Perspectives will be there for the entire conference (the pre-conference workshops have already begun) and among the sessions I look forward to is “Comparative Effectiveness Trials.” I am going to try to blog at least twice during the conference on issues I think are of concern to GxP Perspectives readers. If I am super industrious maybe I will blog from the ACRP Global Conference every day.

Here is a new feature that ACRP is offering:ACRP is pleased to announce that for the first time ever, two live-feed Plenary Sessions from the ACRP Global Conference & Exhibition will be broadcast FREE of charge. Join us May 1 for the Regulatory Affairs Public Forum featuring representatives from global regulatory agencies addressing issues facing clinical trials. Join us May 2 for Innovation & Global Health, a discussion by Tachi Yamada, MD, President, Global Health Program, Bill and Melinda Gates Foundation.

For more information visit the ACRP Website on the Plenary Sessions

ACRP clinical trials

Do You Have a Guest Commentary for
GxP Perspectives?

Another highlight will be the May 1st session on “Your Site Doesn’t Need 60 SOPs, But How Many Does It Need?” The speakers are Christine Pierre, RN and Steven Steinbreuck, MPH and the author of a Guest Commentary on GxP Perspectives on Informed Consent Requirements. Remember, I am always looking for a good Guest Commentary. Send me a note and ask me how-

Leave a Comment to Submit a Guest Commentary!

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On the Blogroll: Top 40 Websites (and Tweeters) on the FDA, by FDAZilla (Yes, we made the list.)

Moriah Consultant’s Blog – Commentary by Michael Hamrell, one of the conference speakers
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Conferences: Pharma/Bio Boot Camp on the eTMF on 20-21 May 2011 in Philadelphia


FDA Clinical Trials: Quality Considerations for Pivotal Studies

April 9, 2011

clinical trials considerations pivotal

When Should Quality Begin?

When should quality preparation begin for a pivotal phase III clinical trial? About once a month I get a call asking for help for a clinical trial because its time to get ready for FDA inspections. I ask “When will the application be filed?” The response? “Soon, very soon.”

It is a good thing to prepare for an FDA inspection. It is even better to prepare at the beginning, reviewing the quality considerations necessary to do the job right by “frontloading quality.” Here are some things I think you should consider. (Please take the survey at the end)

Phase III Considerations for Compliance with the FDA Bioresearch Monitoring Program: by Carl Anderson

The U.S. Food and Drug Administration conducts inspections of clinical trials as part of their Bioresearch Monitoring program. Although all FDA regulated clinical trials are subject to inspection, the large majority of inspections are the result of an application for the approval of an investigational product. Results of an FDA “Bimo” inspection can have a direct impact on the review and approval of an NDA, PMA, or BLA by the agency. FDA conducts inspections of clinical trials for two primary reasons:

1. To ensure the integrity of data submitted to the agency in support of an application.

2. To protect the safety, rights, and welfare of human participants in clinical trials.

The regulations that the FDA enforces for clinical trials are collectively known as the good clinical practice (GCP) regulations. They include 21 CFR Parts 11, 50, 54, 56, 312, 314, 601, 812, and 814. They can be found on the web at: http://www.fda.gov/oc/gcp/regulations.html. In particular FDA Bimo inspections cover the specific responsibilities required of sponsors and investigators covered by 21 CFR 312 Subpart D: Responsibilities of Sponsor and Investigators. For medical devices they are contained in Part 812.

The primary guidance document used for GCPs is the International Conference on Harmonization E6: Good Clinical Practice: Consolidated Guidance. This document is the international standard and the primary GCP regulation in many countries. ICH documents for clinical studies including E6 can be found at the link on the bottom

There are two types of GCP inspections that are of concern for sponsors. The first type is the inspection of clinical investigators at the sites where research is conducted. The majority of FDA inspections are of the investigators. The second type is the inspection of the sponsor or contract research organization. This is a routine inspection for medical device sponsors and is becoming more common at drug sponsors. Although most inspections are at clinical sites, in the event that serious deficiencies are documented, there can be directed inspections of sponsors that can result in serious regulatory action.

clinical trial consideration pivotal

QA for the Data Lifecycle

Prior to beginning a pivotal study the sponsor should establish a system of clinical quality assurance. This is a recommendation, not a requirement, of FDA. E6 defines quality assurance (QA) as: “All those planned and systematic actions that are established to ensure that the trial is performed and the data are generated, documented (recorded), and reported in compliance with GCP and applicable regulatory requirement(s).” Among the most important QA activities are the following:

Clinical trial materials. They should be produced in compliance with good manufacturing practice (GMP) regulations and qualified by an onsite audit.

pivotal clinical trial

Increased Enforcement of
Part 11

Computerized systems including eCRFs. There are many forward looking systems available for electronic case report forms (CRFs) including systems that are internet based. These vendors are not regulated by FDA and do not receive regulatory inspections. The burden is on the sponsor to determine if the vendor provides GCP compliant services. All should be qualified by an onsite audit.FDA has started looking a lot closer at eCRF systems.

Site management organizations (SMOs). These are unregulated organizations that provide support for clinical investigators and recruit study subjects. FDA inspections of sites using an SMO have frequently been cited for noncompliance with GCPs. SMOs should also receive onsite audits.

Central IRBs. These commercial institutional review boards have a better record than SMOs. However, the protection of human participants in research is a central FDA concern. Commercial IRBs should be qualified by an onsite audit.

Randomization services. This might not require an onsite audit and qualification, but the sponsor needs to critically determine that the vendor can supply the required services.

pivotal considerations for phase III clinical trials

QA Audits of Clinical Sites

Audits of clinical sites. ICH E6 states that: “The sponsor’s audit plan and procedures for a trial audit should be guided by the importance of the trial to submissions to regulatory authorities…” The sponsor should audit a pivotal clinical trial throughout the data lifecycle. In particular the sponsor should audit problematic sites during the study. It is the sponsor’s responsibility to “secure investigator compliance” if the investigator is violating GCPs. This was the first violation cited on the Sanofi-Aventis Warning Letter and has historically been a major violation cited on FDA Warning Letters to sponsors.

Top enrolling sites should always be audited during the course of the study because of their increased importance for a successful study and the likelihood that the site will receive an inspection by FDA. The sponsor should also audit sites that may be inspected by FDA at the conclusion of the study including data outliers, sites with a history of noncompliance, and sites that do not have a history of FDA inspections.

Database audits The sponsor’s data management activities should have independent QA review. This should include a qualification audit if data management is contracted out. An excellent resource for data management is the Society of Clinical Data Management. They publish a Good Clinical Data Management Practices Guide which is available for purchase on their website below.

Trial master file (TMF) audits: A TMF consists of the Essential Documents section of ICH E6. There should be QA review periodically throughout the study. The failure to adequately document a clinical trial will hinder any application to FDA. The agency field investigators have a saying that, “If it isn’t documented then it didn’t happen.” Take a look at the TMF page at the top of the blog for additional resources.

Pivotal clinical trial considerations

Conduct Regular GCP Training

GCP training: The sponsor should have a training program that includes initial and continuing training on good clinical practice. The training program should be in writing and training should be documented. At least once a year staff members should attend an outside conference, meeting, or workshop that includes clinical trial professionals that are not the sponsor’s employees.Peer-to-peer interactions are necessary to develop staff

GLP audits: The FDA conducts routine surveillance audits of nonclinical test facilities. An FDA inspector may randomly select a study of the sponsor to track as part of that inspection. Protocols and final reports are collected and sent to FDA headquarters as part of the inspection. The sponsor should always qualify a nonclinical laboratory used for GLP studies submitted to the agency. The new FDA Sponsor Compliance Program (see previous post) gives instructions for looking at nonclinical studies during GCP inspections at the sponsor.

Sponsor audits and mock FDA inspections

pivotl phase III clinical trials

Always Prepare for an FDA Inspection

Finally, a sponsor should conduct audits of their clinical management department and conduct “mock FDA inspections” in preparation for the regulatory audits that will inevitably take place after the NDA, PMA, or BLA is filed. Preparing for a regulatory inspection is invaluable for effectively hosting any regulatory agency, in particular FDA. Medical device sponsors need to remember that FDA typically inspects sponsors submitting a PMA. Drug sponsor inspections are on the increase. The “OAI” violation rate for inspections of medical device sponsors was 33% in fiscal year 2007. OAI stands for “official action indicated” the most serious classification.

An OAI classification can cause FDA to delay or reject an application.

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This just in: Request for Comments- Exculpatory Language Used in Informed Consent, a joint FDA and OHRP draft guidance document (September 2011)

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Society for Clinical Data Management

ICH Guidance Documents
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On the Blogroll: PharmTech Talk has had a number of interesting blog posts of late.
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FDA clinical trials pivotal studies

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CAPA Plans for Clinical Trials

February 22, 2011

GCP CAPA Plans for clinical trials

CAPA Plans: Corrective and Preventative Actions

CAPA- corrective and preventative action– Are CAPA plans for clinical trials different than a CAPA for a GMP quality system? Do GCP regulations require CAPA plans? Is a root cause analysis necessary to develop a CAPA plan? What are FDA’s expectations for CAPA plans? These are some of the questions that were asked at EXL Pharma’s conference on CAPAs in the clinical trial environment held last month in Virginia. I then had the opportunity to ask them all over again during a “for-cause” GCP audit. The results provided for some interesting insight into how sponsors, CROs, and clinical investigators can investigate errors in clinical trials and put in place a process to prevent the errors from continuing.

First we should define our terms:

Corrective Action: –Immediate action to a problem that has already occurred or has been identified.

Preventative Action= Taken to eliminate the root cause of a potential problem including the detection/identification of problems.

Root Cause Analysis: A class of problem solving methods used to identify the root causes of problems or events.

These definitions hold true for all GxP quality systems. However, there are some basic differences that set GCP CAPAs apart from the manufacturing or GLP arena:

= FDA regulations assign responsibilities to Investigators, Sponsors, & IRBs- there are NO regulatory responsibilities for human subjects participating in clinical trials

= GMPs involve a manufactured product- GCPs involve a clinical investigation, an experiment- The “products” are the integrity of the data and the protection of human subjects in clinical research.

= GMPs largely involve a manufacturing process- GCPs largely involve the interactions of People

CAPA Clinical Trials

What is the Root Cause of the Problem?

FDA has made it clear both in public presentations and in Warning Letters to sponsors and clinical investigators that they expect two responses to GCP problems once they have been identified. First, there should be an investigation regarding how widespread the problem is. In effect, conducting a root cause analysis and investigation into the problem. Next, FDA expects a description of efforts into the prevention of the problem in the future. This is essentially a plan of corrective and preventative action, a CAPA. So even though FDA’s GCP requirements don’t specify CAPA plans, if you receive a Form FDA 483, Inspectional Observations, you really need to put a CAPA plan into place. Here are two examples why:

= FDA Sponsor Warning Letter, January 2011 – “Your response is inadequate in that it does not describe your corrective and preventive actions in sufficient detail.”

= FDA NIDPOE letter to Clinical Investigator (potential disqualification warning) 2009: “…however, you failed to investigate for additional acts of falsification within the same clinical investigation or in other clinical investigations in which the study coordinator was involved.”

CAPA clinical trials

Always Look for at Least 2 Root Causes

The root cause analysis of a clinical trial problem should include an investigation into what happened. Different problems will need different levels of investigation depending on significance. In addition, the root cause analysis will need to determine if a CAPA plan is required. Not all problems or errors are both systemic and significant. You don’t want to institute a system of “Death by CAPA” by initiating a CAPA plan for each error that occurs. People make mistakes and a quality system should focus on the errors that matter. Sometimes you will see a “CAPA” that merely restates the error and then the ubiquitous note to file saying “retrained study coordinator.” This is not an appropriate CAPA plan and not an appropriate corrective action. Here are some points to include in a CAPA investigation:

= There can be multiple root causes- Always Look at Two Possible Root Causes

= “Always look at the raw data.” If you are not looking at original documents, then you are missing something of importance

= Why, why, why, why, why The “five why’s” of CAPA. Drill down to find the root cause.

= The “root cause” is not restating the error.

= PICCC: Problem, Investigate, Comparison, Clues, Cause

CAPA clinical trials

Problem Solving in Clinical Trials

PICCC is a useful tool in a root cause analysis. What does “comparison” mean? It means to compare the problem across protocols and across clinical sites. If you have the failure to follow a point in the protocol at one site, do other sites have the same problem? If that is the case, the root cause may very well be that the protocol is poorly written, it may need an amendment. The corrective action would not read, “retrained study coordinator on the importance of protocol adherence.” The CAPA plan would look in a different direction, towards the sponsor. The ubiquitous note to file may not be necessary.

There is a wealth of resources on CAPA, root cause analysis, and conducting an investigation. I am including some of those that I used for this post as well as for presentations. There is still a lot to be developed on CAPAs for clinical trials. However, it is clear that regulatory agencies want to know what you have done to investigate clinical problems and what you are doing to prevent them from recurring. In short, they want CAPA plans.

Barb Immel on CAPA Investigations

Essential Components of an Effective CAPA Plan by Jim Colyn

Root Cause Analysis by Edward Dunn, MD

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GxP Audit & Risk Management Congress: 20-21 October 2011, Philadelphia, PA. This conference combines both GMP and GCP tracks to maximize the opportunity for cross training, shared best practices, and networking. Two members of the GxP Perspectives LinkedIn group, Janice Wilson and Adi Lampmann, are among the faculty. The conference is sponsored by ExL Pharma and GxP Perspectives is a media partner.
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SPECIAL UPDATE: 18MAR2011: FDA has released an updated version of the Compliance Program Guidance Manual 7348.810, Sponsors/Contract Research Organizations/Monitors. There are new sections on registration of clinical trials on ClinicalTrials.gov, Financial Disclosure, the Part 11 Scope & Application Guidance Document, and other issues. If you work for a sponsor, a CRO, or are a contract CRA you MUST read this document. Review Section III, Inspectional.

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