Three Things That You Should Know About Part 11

June 4, 2012

Part 11

Three Tips on Part 11

What is FDA doing about Part 11? Is the regulation for electronic records and electronic signatures still in force? – The answer is YES – What, if anything, should my company or clinical site be doing about it. Strict compliance can be very expensive- almost as expensive as no compliance at all! Here are three tips on Part 11 compliance from veteran consultants and regular GxP Perspectives contributors, Emma Barsky and Len Grunbaum. I first met Len at the last FDA training course I attended as an FDA field inspector. He is still training FDA and Industry on computerized systems. Given that FDA is focusing more and more on the automated processes and integrity of the data collected using automated means, Part 11 is more important than ever.

Carl Anderson, GxP Perspectives

GUEST COMMENTARY
Three things you need to know about 21 CFR part 11
by Emma Barsky & Len Grunbaum

Fifteen years after becoming effective, 21 CFR part 11 seems to generate as much controversy as it did when it was first implemented. At this point in time, we cannot think of another regulation that sparks as many disagreements with respect to its interpretation and generates as many discussions. Why is that?

Since the inception of the regulation as of August 1997, compliance has been, in our view, analogous to the story of Goldilocks and the Three Bears: compliance in some companies has been too hot (i.e., too restrictive and expensive); compliance in some companies has been too cold (i.e., minimal if any at all); and, compliance in some companies has been just right (i.e., cost-beneficial and based on an effective risk assessment). So, while we do not in any way want to equate compliance with the regulation to a bowl of porridge, we hereby offer three main things that you need to know about 21 CFR part 11 to help you make your compliance just right:

PART 11

THE IMPORTANCE OF VALIDATION

1. You need to know how to assess risks when it comes to 1) developing a validation approach regarding a given system and 2) implementing controls (e.g., audit trails, logical/physical security) to help ensure the trustworthiness and reliability of the records. As indicated in the Scope and Application guidance, the FDA’s “current thinking” on the subject, the agency will expect you to have a justified and documented risk assessment regarding these items. However, in order for the respective strategies and controls to be cost-beneficial in context of the potential of the system to affect product quality and safety, and record integrity, a combination of knowledge of system functionality, regulatory understanding, financial prudence and a healthy dose of common sense are required. Take one of these elements out of the equation and the resulting risk assessment will be neither practical nor useful.

2. You need to know the minimum documentation that must be available to support compliance with 21 CFR part 11. Irrespective of the development model employed (e.g., waterfall, Agile/Scrum), the software delivery model employed (e.g., software-as-a-product, software-as-a-service) or data hosting model employed (e.g., internal data center, outsourced hosting), as applicable, a documentation suite that truly supports compliance should encompass the following:

• User/functional requirements, including 21 CFR part 11 requirements, to describe what the system is supposed to do;

• Technical specifications to define how the system is built and how it works, and which is the critical component in supporting effective system maintenance (e.g., troubleshooting problems, assessing the impact of planned bug fixes and enhancements);

• Development/validation SOPs, and evidence of compliance (e.g., required documentation, required approvals, developer-level and user acceptance testing), to define the process for developing and deploying a system that operates as intended and meets regulatory requirements;

• Traceability between test evidence and all requirements;

• Change control SOP and supporting change request/change control records to ensure that the system continues to operate as expected;

• Training SOP and supporting training records to support staff qualifications regarding system development, maintenance and use;

• IT infrastructure SOPs (e.g., logical/physical security, back-up and recovery, etc.) and supporting records to evidence on-going protection and availability of records.

3. You need to know that, for a given system, the quality of testing and quality of reviews are of paramount importance because they may compensate for ineffective development and/or validation SOPs. In other words, the devil (or in this case the saving angel) is in the details. Therefore, it is important that

• Testing is complete and reflective of true system risks;

• Test evidence is supportive of test results/conclusions and/or does not raise “red flags”;

• Reviews are timely and reasonable (e.g., only a realistic number of detailed test scripts should be reviewed in one day);

• Incident reports are reviewed and approved by appropriate individuals promptly.

If testing practices, testing evidence and/or testing reviews are questionable, they will constitute a serious gap from a risk-based perspective because 1) one may not be able to rely on the given system’s operation, results, etc., and/or 2) data quality and integrity may be viewed as being compromised.

Part 11

Is your Compliance Running Too Hot or Too Cold?

While there are other aspects to 21 CFR part 11 that one should know (e.g., how to determine if 21 CFR part 11 even applies to you and, if not, how to document such a conclusion), the three items discussed above represent those areas where, in our view, compliance tends to be too hot (i.e., potential business risk in that the cost of doing business may be higher than it should be) or too cold (i.e., a potential regulatory risk in that regularity requirements may not be met which, in turn, may result in business risks based on the operational impact of FDA enforcement actions).

Emma Barsky and Len Grunbaum
Partners of The Practical Solutions Group, LLC
609.683.0756
Practical Solutions

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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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FDA & Politics: In the Interest of Science?

April 3, 2012

FDA and politics

Political Pressure at FDA?

FDA Regulates 25% of the U.S. economy and has long been the target of lobbyists from the food,drug, & tobacco industries.The question is always asked: “Is mixing the public health mission of FDA with politics in the current political climate advancing the interests of the American consumer?” Unfortunately, the answer is almost always no. Last December GxP Perspectives published a Guest Commentary on “when Politics and Science Collide,” by April Mayberry. In the 03 April 2012 New York Times there is an extensive page one article on the differences between the Obama White House and FDA on public health issues.

For most readers of this blog it is a question on the approval of health products; drugs, medical devices, and biologics, that come to mind. Is FDA providing the right balance in regulatory oversight? Is FDA making decisions based on science and not political pressure? The issue came to a head over the Plan B controversy that April Mayberry wrote about in her Guest Commentary. In this week’s FDA Matters, longtime FDA observer Steven Grossman talks about different plans to speed up FDA approvals noting that there are rarely initiatives to make sure that FDA scientists have the time and resources to make the right decisions. Grossman notes that former FDA Commissioner Dr. Andrew Von Eschenbach wrote an opinion piece in the Wall Street Journal where he states:

FDA and Politics

Dr. Andrew Von Eschenbach

“What will it take to realize the potential of the new medicine? The United States has the world’s most innovative drug and device companies and research universities, plus the unparalleled National Institutes of Health. What’s missing is a modernized Food and Drug Administration that can rapidly and efficiently bring new discoveries to patients.”

This places the burden, and blame, for new health product approvals squarely on FDA. The New York Times article points out that political pressure has often shaped FDA policy and that there have often been serious consequnces when FDA tries to assert its independence. For example, FDA Commissioner Dr. Jane Henney lost her job for allowing the approval of the controversial drug RU-486. Although then DHHS Secretary Donna Shalala guaranteed Dr. Henney that FDA would have independence to make scientific decisions, she was soon out of a job with the election of George W. Bush.

FDA and politics

Dr. Margaret Hamburg has Supported FDA Scientists on Plan B

Current FDA Commissioner, Dr. Margaret Hamburg has not had as supportive a relationship with the current DHHS Secretary, Kathleen Sebelius. They clashed on the restrictive measures insisted on by Secretary Sebelius for access to Plan B. Other areas of disagreement include labels on sunscreens and over the asthma drug Primatene Mist. In an election year the volatile mix of politics and science is even more apparent. In the New York Times article FDA historian Daniel Carpenter of Harvard University warns:

“In a globalized world , where trust is a huge part of what American manufacturers have to sell, the politicalization of the FDA’s reputation could hurt not only consumer protection but industry profits as well.”

It should be an interesting year for science and politics.

Carl Anderson, GxP Perspectives

Read the New York Times Article

FDA Matters

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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

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FDA Warning Letters for International APIs in 2011

January 8, 2012

API FDA Warning Letter International firms

API Warning Letters to International Manufacturers

FDA issued at least ten Warning Letters to international manufacturers of active pharmaceutical ingredients in FY-2011. Manufacturers in both China and India, the world’s largest exporters of APIs, received three Warning Letters each from FDA. Manufacturers in Spain, the UK, Canada, and Japan each received one Warning Letter from FDA. These metrics show both the domination of China and India in the API market as well as the continued dependence on international manufacturers for APIs destined for the U.S. market.

Deficiency Categories:

The violation that dominated the charges cited by FDA in FY-2011 related to quality control, cited in four Warning Letters, two to China and one each to Canada and Japan.

FDA API Warning Letters in 2011

Failure to Have Procedures for Cross Contamination

Another violation that is sure to cause concern with FDA is the failure to prevent cross-contamination. When I attended FDA API inspection training in 2000 cross-contamination, particularly with anti-biotics, was a major concern. It continues to be with API manufacturers in both India and China being cited for the “Failure to have appropriate procedures in place to prevent cross-contamination.”

Out of specification (OOS) laboratory results are always a concern of FDA and landed on Warning Letters to manufacturers in India and Spain. Other citations include:

= Water purification for APIs used in parenterals

= Failure to establish a stability program to monitor APIs

= Failure to perform at least one identity test of each batch of incoming material

= Validation of analytical methods used to test APIs

There are no big surprises here but it shows that regular surveillance of API vendors is an absolute necessity for the manufacture of quality drug products. What is of interest is that GxP Perspectives couldn’t find any domestic Warning Letters for APIs. That doesn’t mean they don’t exist, only that they couldn’t be easily located. Unfortunately, FDA lists API Warning Letters in any number of classifications for GMPs for finished pharmaceuticals. However, they don’t seem to list them for APIs. With all the razzle-dazzle taking place on FDA’s website, you would think they could come up with a consistent way to list API Warning Letters. Who knows, maybe next year.

by Carl Anderson, GxP Perspectives
Research by Francesca Carreras-Perez, GxP Perspectives

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Two articles of interest regarding APIs:

Indian API Manufacturers want anti-dumping duties

API Product List (note countries of origin)

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Commentary on Plan B Controversy

December 28, 2011

Plan B Kathleen Sebelius

Kathleen Sebelius Overturns FDA on Plan B

Plan B is an emergency contraceptive, sometimes called “the morning after pill,” that has been approved as safe and effective for its intended use by the Food and Drug Administration. The drug’s safety is pretty much beyond dispute. However, it is access to Plan B that is proving controversial. In question is whether Plan B can be available over-the-counter or on a prescription basis for all women of child-bearing potential. This includes those under 18 years of age. FDA had said yes. In an unprecedented decision, the Secretary of Health and Human Services, Kathleen Sebelius, overturned a decision by FDA. The decision, in early December, has largely been overlooked by the general public with the onset of the holidays and college football bowl games. However, it has profound implications for millions of Americans and perhaps the way FDA approves drugs in the future. FDA Commissioner Margaret Hamburg issued a public statement after the decision defending FDA’s scientists who had recommended the OTC approval (see below).

The following Guest Commentary by April Mayberry discusses this decision. In it she gives her opinion on the Plan B decision. GxP Perspectives, as always, welcomes your own viewpoints and opinions.

When Politics & Science Collide

Plan B

Plan B Emergency Contraception

As a clinical research professional working in women’s reproductive health and contraceptive development, I was disturbed by Dr. Sebelius’ decision to override the FDA’s decision to allow OTC access to Plan B for girls under 17. First my reaction was concern about the impact this will have on women and contraceptive development. Second was to wonder why Dr. Sebelius, an Obama appointee with a strong reputation for supporting reproductive rights, would make such a decision.

In her statement posted on the HHS website, Sebelius said that Teva didn’t provide sufficient evidence that Plan B could be used safely in very young adolescent girls, or that they could understand the labeling. She said if Teva could produce data to the contrary they could refile. If Sebelius’ decision was intended to protect girls, it doesn’t seem logical.

• An adolescent girl has a much higher chance of serious complications from an unintended pregnancy or an abortion than from Plan B.

• Other potentially dangerous OTCs used, and even abused, by young women have no such restrictions. This includes diet pills, cold medicines, aspirin, ibuprofen and acetaminophen, all of which are associated with serious and/or fatal AEs.

• In my experience, controversial products not indicated to treat immediately life-threatening conditions must meet a particularly high approval standard. In a public statement appearing on the FDA website, FDA Commissioner Margaret Hamburg said:

“The Center for Drug Evaluation and Research (CDER) completed its review of the Plan B One-Step application and laid out its scientific determination. CDER carefully considered whether younger females were able to understand how to use Plan B One-Step. Based on the information submitted to the agency, CDER determined that the product was safe and effective in adolescent females, that adolescent females understood the product was not for routine use, and that the product would not protect them against sexually transmitted diseases. Additionally, the data supported a finding that adolescent females could use Plan B One-Step properly without the intervention of a healthcare provider.” In the same statement Dr. Hamburg contended that:

Dr. Margaret Hamburg, FDA Commissioner

Dr. Margaret Hamburg, FDA Commissioner

“The review process used by CDER to analyze the data applied a risk/benefit assessment consistent with its standard drug review process. Our decision-making reflects a body of scientific findings, input from external scientific advisory committees, and data contained in the application that included studies designed specifically to address the regulatory standards for nonprescription drugs. CDER experts, including obstetrician/gynecologists and pediatricians, reviewed the totality of the data and agreed that it met the regulatory standard for a nonprescription drug and that Plan B One-Step should be approved for all females of child-bearing potential.”

So if FDA used the standard review process why isn’t it enough? Most agree this decision was not based on science. One can only speculate why Sebelius, an Obama appointee, with a strong record regarding women’s reproductive rights, would do this. Possible reasons that come to mind are:

There has been pressure from the religious right on the government against Plan B and contraceptives in general. Plan B is of particular contention, because some mistakenly believe that it terminates pregnancy. Reportedly while governor of Kansas, Sebelius at times modified policy under pressure when it was seen as a political advantage
(also reportedly in these instances the decisions didn’t pose a risk of clinical or other harm to women. In light of reports that she is a subject of backlash by the church.) and of a lawsuit by Belmont Abbey College over the mandate requiring them to provide contraceptive coverage in their health plan, it’s feasible OTC access to Plan B for girls under 18 was sacrificed in lieu of mandates Sebelius considers more crucial, such as requiring health-care plans to provide contraceptive coverage. (Sources: RealityCheck.org, National Catholic Register, and Washington Times)

Plan B access

Should Teenagers Have Access to Plan B?

Regardless of the actual motives behind this move, it has a real potential for negative ramifications. Requiring a young girl to consult an HCP (most having limited office hours) poses potentially insurmountable obstacles to accessing Plan B in the time it’s most effective, possibly resulting in an unintended pregnancy. She must have access to an HCP, know how to navigate the system, have transportation and maybe money. For a young woman who is in a dysfunctional situation or is victim of sexual abuse, these barriers could compound their duress and risk, especially if a pregnancy resulted.

Women over 17 are also affected. Having to present an ID to a pharmacist can cause distress for some. Additionally many pharmacies have limited hours, and in some states some pharmacists may refuse to provide Plan B under the “conscious clause”, all causing delays in accessing it within the optimal treatment window. This is of particular concern for poor women in some rural or inner city communities with few pharmacies and for women with no ID.

Sebelius’ decision may also stifle contraceptive development. According the New York Times this is the first time that the HHS has blocked approval of a product by the FDA. This sets a precedent, allowing approval of contraceptives or other controversial medical products to be blocked without scientifically valid reasons. This is very problematic, because it allows those with political motives to take our national policies and the scientific process hostage to fulfill their own agenda, simply by applying enough political pressure.

April Mayberry, RAC, CCRA, CCRP, CFPHW *

* Certified Family Planning Health Worker

Dr. Hamburg’s Statement on Plan B

Secretary Sebelius’ Statement on Plan B

Pharmacist “Conscious Clause”

NT Times article on Sebelius curtailing availability of Plan B

National Catholic Register Article on Sebelius

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January GCP Training Opportunities:

ExL Pharma has announced that FDA’s Dr. Leslie Ball will give the Keynote Address at the 2nd annual Developing CAPAs in the GCP Environment conference held 19-20 January in Arlington, VA.

GxP Perspectives is a media sponsor.

At the same time and the same place the Trial Master File Summit is taking place with some excellent speakers. Find out more:
TMF Summit Information

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GxP Perspectives LinkedIn Group

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Please comment with your views and opinions!

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A Better FDA? Why Not?

December 11, 2011

FDA

A Better FDA?

Is FDA necessary? Most people I know would say yes. We need a strong, independent, effective FDA. Does FDA need improvements? Again, most people I know can point to numerous issues that FDA could handle better. Today, in the Business Section of the New York Times, there is an article on why we need government and the benefits of better government. Yes, the article by Robert H. Frank is about the Tompkins County New York Department of Moter Vehicles, but he outlines some basic principles for better government. Like better use of technology to make government more efficient. FDA is making similar efforts regarding technology. That’s great and I encourage the development. Here are three other areas that I think that FDA can improve:

1. Consistent training for field investigators (CSOs or Consumer Safety Officers). Many times people tell me of an FDA inspection in Salt Lake City that is entirely different from another inspection I have heard of in Tampa, FL. Different CSOs have completely different approaches and conduct the same type of inspection by looking at completely different documents. There are many excellent, experienced CSOs but when different clinical sites or sponsors hear differing viewpoints from CSOs, that isn’t good for compliance or best practices.

2. Changing requirements by review divisions. FDA will tell a sponsor to conduct a study with certain endpoints in order to prove safety and efficacy for their investigational product. Then, as the sponsor is preparing for their application, the rules change. This can cost a sponsor years of frustration and millions of dollars. Yes, safety concerns need to be addressed, but sponsors need to know the rules in advance, and have a reasonable expectation of those rules staying in place.

3. Effective mechanisms for corrective actions. FDA has a Warning Letter close out process. However, it is not evenly applied by different Centers and for different program areas. Regulated industry should have a clear path to performing corrective actions that are meaningful.

So those are my thoughts. I would love to hear yours. Please leave a comment.

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One additional point: My wife, Cathy J. Tashiro, just had her book come out in paperback. No, it has nothing to do with GxPs or clinical trials, she is a sociologist. Her book is:

Standing on Both Feet: Stories of Older Mixed Race Americans

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Read the NY Times article on effective government

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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

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FDA 483s: Effective Responses to Avoid Warning Letters

October 16, 2011

Responding to FDA 483

Effective Responses to Form FDA 483

An FDA inspection can result in a Form FDA 483, Inspectional Observations, being issued by the FDA field investigator. How you respond can determine whether the 483 will result in a Warning Letter, the primary form of FDA enforcement actions. How to respond to a 483 is a topic of discussion for regulated industry since the 483s arose in the early 1950s, originally as an attempt by FDA to respond to industry complaints that FDA didn’t inform industry about the field investigator’s findings prior to initiating an enforcement action (at the time primarily seizures, injunctions, and prosecutions). In this Guest Commentary regular GxP Perspectives contributors Emma Barsky and Len Grunbaum list the problems that FDA has found with responses to 483s and some proposed solutions.

Guest Commentary: One Way to Avoid a Warning Letter … Maybe

The following sentence fragments represent but a very small sample of trumpet calls heralding that a firm may have fumbled an opportunity to avoid a Warning Letter after receiving an FDA-483:

• “We have reviewed your response and have concluded that it is not adequate because…”

• “The adequacy of the response cannot be determined because the response did not include…”

• “Your response does not address…”

• “We have reviewed your firm’s response and note that it lacks sufficient corrective actions regarding…”

• “We have reviewed your firm’s responses; however we continue to have concerns related to your firm’s compliance…”

• “The adequacy of your firm’s response cannot be determined at this time…”

• “Your response is inadequate because…”

We say this because of the following: while a response to an FDA-483 is not mandatory and does not represent a final Agency determination regarding firm’s compliance, a firm’s voluntary response often does impact the Agency’s conclusion of the need for follow-up actions, one of which may be the much feared and dreaded Warning Letter. How so, you ask? Here is how….

FDA 483s and Warning Letters

"FDA will conduct a detailed review"

As the FDA indicates in section 5.2.7 of the Investigations Operations Manual, “If FDA receives an adequate response to the FDA-483 within 15 business days of the end of inspection [emphasis added]”, FDA will conduct a detailed review of the response before determining whether to issue a Warning Letter. Alternatively, responding late negates any chance that the FDA will consider the firm’s responses in its resolution regarding whether a Warning Letter is warranted and not responding at all, of course, has the same outcome as responding late.

This brings us to the quality of the response itself. In this context, the higher the “quality” of the response, the more likely the FDA will consider the response as “adequate” and, as a result, may not issue a Warning Letter. Since the firm’s management controls the quality and timeliness of everything that goes on, we suggest that the following guidelines be used to craft the response to the FDA-483 to increase the firm’s chances of avoiding the Warning Letter:

• Train the individuals involved in the FDA-483 response effort regarding what information should be included in the response and the format chosen to present the response.

• Assign someone to review recent FDA Warning Letters to identify those items where the FDA indicates that the response to the respective FDA-483 was not adequate and include these items in the training to ensure that known mistakes/failures are not repeated.

FDA 483 response

Focus Your Response

• Focus on evaluating the extent of the observation in terms of whether the issue could have potentially impacted data integrity, and, if so, whether the issue is systemic (e.g., how many studies, batches, sites, etc. could be possibly affected). This is the most important point to address in terms negating the observation or softening the impact of the observation. If an observation points to actual data integrity issues, these issues need to be brought to the attention of the respective sponsors, where applicable, and responses to the FDA should be discussed with them first.

• Establish the true root cause of the observation. In doing so, look for the operational gap (e.g., inefficient project management oversight) that resulted in the regulatory deficiency (e.g., lack of timely document reviews and/or approvals) so that it can be fixed properly and permanently.

• Provide specifics regarding any corrective actions taken or proposed. It is not adequate to state that the problem was or will be corrected. Details regarding 1) what was/will be corrected (e.g., development of a remediation plan), 2) when it was/will be completed and 3) if applicable, the timeframe for training (e.g., as in case of a revised procedure) should be provided.

• Describe preventive actions that will minimize or eliminate the chance of recurrence of the problem in the future.

• Provide supporting documentation for every claim made.

• Show commitment regarding implementing all of the proposed activities by 1) specifying activities to be taken and target dates for their completion, 2) assigning accountability for the actions, 3) ensuring proper completion of each respective activity though internal audits.

effectively responding to a 483

The Importance of a Quality Response to FDA 483s

The quality of the response to the FDA-483 is also important for another reason: groups like FOI Services request the Establishment Investigation Reports (EIR) and FDA-483s through the FOIA, so this information eventually winds up in the public domain.

The firm can request that its FDA-483 response be published along with the FDA-483 itself, in which case the response should be such that it gives confidence not only to the FDA but also, where applicable, to existing and potential clients, that non-conformities have not and do not impact data integrity.

The bottom line is this: Do not ever get yourself in trouble with the FDA. But if you do, avoid unforced errors by 1) taking the time and making the effort to respond to the FDA-483, if you get one, in a timely fashion, 2) using the guidelines above in doing so, or 3) consulting with an expert to assist.

By Emma Barsky and Len Grunbaum, the partners of The Practical Solutions Group, LLC

Contact Emma & Len

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ExL Pharma has announced that FDA’s Dr. Leslie Ball will give the Keynote Address at the 2nd annual Developing CAPAs in the GCP Environment conference held 19-20 January in Arlington, VA. GxP Perspectives is a media sponsor.

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Read FDA Warning Letters A suggested practice is to search Warning Letters by topic or issuing office. Then sort by “Letter Issue Date – Desc” to find the most recent Warning Letters.

19 October 2011 update: FDA posted a Warning Letter to SmithKline Beecham (GSK), West Sussex, UK for serious cGMP violations stating: “Your firm has not established appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile.”

Read the Warning Letter

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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. I invite everyone to join the GxP Perspectives LinkedIn Group and join the discussion.

GxP Perspectives LinkedIn Group

GxP Perspectives on twitter: @GxPPerspectives
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On The Blogroll: Rebar Interactive (twitter: @rebarinte) has an excellent blog for clinical sites. If nothing else you MUST 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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