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


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.


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.

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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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PI Training & Qualifications: FDA Draft Guidance

October 9, 2011

FDA guidance on risk-based monitoring

PI Training & Qualifications

One of the issues raised by the new FDA Draft Guidance on Risk-Based Monitoring is the training and qualifications of clinical investigators, usually referred to as the PI. Veteran GCP training specialist David Montgomery questions whether the draft guidance document is consistent with the previous final guidance document on Supervisory Responsibilities of the Investigator (2009). David raises some interesting points as he enlivens the discussion on the draft guidance. Since this is a significant change in how FDA is giving its current recommendations on monitoring, it deserves a certain amount of scrutiny. And David is certainly up to the task, with a Latin lesson thrown in for good measure!

Guest Commentary by David Montgomery

Facile Descensus Averno

This latest proposed guidance from the FDA is a constructive move forwards but like the ancient Greeks seeking guidance at the Oracle at Delphi there will inevitably be points for interpretation.

PI training and experience

The Oracle at Delphi

Somewhere between sponsors perception of what the FDA is saying and the guidance they actually provide lies a vast expanse of mythology which can, on occasion, be attributed inappropriately the badge of best practice — itself a context specific judgement in an increasingly global enterprise. It is axiomatic that the FDA is taking a stance by providing its current thinking and therefore challenging sponsors to apply some critical thinking to their own processes and procedures. Sponsors need to be confident that they the necessary structure in place to enable their staff to fulfil their tasks in accordance with regulatory guidance. Moreover, and at of least equal importance, sponsors need their quality systems to achieve the goals set out in ICH GCP in terms of safeguarding trial subjects and ensuring that credible data are generated.

Certain phrases from the latest guidance stand out and all those involved in the planning, conduct and monitoring of clinical trials of drugs, biologics or devices would do well to take note of these, whilst at the same time recognising that they are not cast in stone.

(all numbered lines are from FDA draft guidance document)Lines 62 – 64 “Quality is a systems property that must be built into an enterprise and cannot be achieved by oversight or monitoring alone.”

Comment: See text from lines 207 – 209

Lines: 97 – 99 “For major efficacy trials, companies typically conduct on-site monitoring visits at approximately four- to eight-week intervals, at least partly because of the perception that the frequent on-site monitoring visit model, with 100% verification of all data, is FDA’s preferred way for sponsors to meet their monitoring obligations”

Comment: we are talking efficacy trials

Lines: 188 – 189 “This draft guidance strongly encourages sponsors to tailor monitoring plans to the needs of the trial”

Comment: One size does not fit all

Lines 207 – 209 “A poorly designed or ambiguous protocol or case report form (CRF) may introduce systemic errors that can render a clinical investigation unreliable despite rigorous monitoring.”

Comment: Attempting to remedy a bad protocol with copious doses of guidance is an exercise in futility and the tale of Sisyphus springs to mind.

Lines 209 – 210 “Study-specific training of investigators, other site staff, and monitors also contributes significantly to study quality (see sections IV.D.4. and VI.A). “

Comment: (209 – 210) What is meant by training?

464 – 469 “Training should include principles of clinical investigations, critical protocol-specific requirements, the study monitoring plan, applicable standard operating procedures, and appropriate monitoring techniques.”

Comment: Protocols have objectives and endpoints – in the interests of quality will training adopt the same model?

Lines 531 -532 “On-site visits should include sufficient time for mentoring, feedback, and additional training, if needed, during the conduct of the study.”

Comment: Feedback is always valuable but how are monitors qualified for study specific mentoring roles or is ICH GCP 2.8 to be ignored?

PI training and experience

"I must take issue with FDA on their use of the term training."

I must take issue with the FDA on their use of the term training. It blurs the responsibilities of what was stated in its own guidance from 2009 for Investigator Responsibilities and what was intended in ICH GCP, particularly in relation to multicentre trials.

The term training is already over used in clinical research, particularly when what is often intended is instruction or guidance. Furthermore, the use of the word mentoring is certainly a bridge too far. This is not what Homer had in mind – in what way are sponsor’s monitors qualified to fulfil these roles or are we going to waive the requirements of ICH GCP 2.8 for those undertaking a role which “contributes significantly to study quality.”

The 2009 FDA Guidance on Investigator Responsibilities takes the trouble to define what they consider necessary in terms of adequate training and puts the onus on the investigator to ensure that there is adequate training for all [their] staff participating in the conduct of the study.”

Compare this to ICH GCP 5.23.4 which states that “All investigators are given instructions on following the protocol, on complying with the uniform set of standards for the assessment of clinical and laboratory findings, and on completing the CRFs.” Interestingly, the purpose of an initiation as it is “To document the trial procedures were reviewed with the investigator and investigators trial staff.”

PI training and FDA risk-based guidance

Providing Instructions or Providing Training?

Providing instructions is rather different to providing training — a point well made Dr Robert Mager, world-renowned expert on training who said, “If telling was the same as training we’d all be so smart that we can hardly stand ourselves.” All those with an over weaning dependence on the use of the weapons of mass instruction, such as PowerPoint, would do well to read his works. But in the context of the training described by the FDA, particularly as it is directed towards clinicians, it is also helpful to consider an article in the British Medical Journal some years ago in relation to the teaching of doctors.

“There has always been an assumption that if a person simply knows a lot about their subject, they will be able to teach it.” Few persons responsible for providing effective teaching and/or training would disagree with this point of view. However, if it is truly the intent of the FDA that sponsors provide training then the latter would be wise to read that BMJ article in more detail, since it goes on to state that “understanding the learning process will help clinical teachers to be more effective.”

The real question is what the FDA expects sponsors to provide: a review of study specific procedures and documents coupled with feedback during monitoring visits, as stated in ICH GCP or training complete with intended learning outcomes and evaluations?
If you employ an architect and a builder to renovate your house you will ask them to provide plans and a schedule of work which comply with building regulations and other applicable regulatory requirements. Reviewing and agreeing their plans prior to implementation coupled with checking on their progress of their work would be the actions of the prudent — yet I wonder how many builders or architects would consider this training?

Fa·ci·lis de·scen·sus A·ver·no    [fah-ki-lis des-ken-soos ah-wer-noh; Eng. fas-uh-lis di-sen-suhs uh-vur-noh] Show IPA
Latin .
(the) descent to hell is easy; it is easy to take the downward path. Vergil, Aeneid, 6:126.

(From Dictionary.com)

Guidance for Industry: Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring

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

Next week: Guest Commentary by Len Grunbaum and Emma Barsky on:
One Way to Avoid a Warning Letter … Maybe

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.

GxP Perspectives LinkedIn Group

GxP Perspectives on twitter: @GxPPerspectives

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On The Blogroll: Rebar Interactive 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.
Please comment on the new draft guidance on Risk-Based Monitoring.

Clinical Trials in India: An Overview

September 25, 2011

India flag map

Clinical Trials in India

India is fast becoming a major center for clinical trials and drug development. The increase in activity has lead the FDA to establish international offices in Mumbai and New Delhi in 2008. FDA states that their mission in India is in part: “… engaging with Indian counterpart regulatory authorities to ensure the timely exchange of information regarding clinical trials that are conducted that support marketing applications in the U.S…” Growing interest in India comes with many questions. What is the history of drug development in India? What type of regulatory structure does India have? What is the infrastructure for clinical trials and drug development? In this Guest Commentary by Jacquie Mardell she gives an overview and discusses some of the benefits, and challenges, of conducting clinical trials in India. GxP Perspectives is fortunate to have a number of readers in India. In fact, after the United States, the country with the most members of the GxP Perspectives LinkedIn group is India. I invite them and others to comment and share their insights about clinical trials in India.

Changes in Indian Clinical Trials Processes Cause for Renewed Enthusiasm

India medical facilities for Clinical Trials

Advanced Clinical Trial Infrastructure

India has become an attractive destination for clinical trials, combining many of the elements western sponsors require: a vibrant urban health care milieu staffed by English speaking professionals with first class medical credentials; an advanced clinical trial infrastructure thanks to the long-standing presence of big pharma companies and major CROs who trained local monitors and project managers in current GCP methodology; the wide availability of high-speed Internet access in offices and hospitals enabling instant remote data capture; and of course relatively easy access to large numbers of willing patients with the conditions western sponsors want to study, such as cardiovascular disease, metabolic diseases such as type 2 diabetes and many types of cancers.

By the early 2000’s, there remained just two significant challenges in conducting Indian clinical trials from the western sponsor’s perspective: shaky intellectual property protection and a long, opaque regulatory process for obtaining clinical trial approval. The former has been resolved by India’s participation as a signatory in WTO’s TRIPS agreement and subsequent harmonizing amendment of her own patent laws in 2005. The approval problem was addressed in late 2006 when India’s regulatory authority, the Drugs Controller General of India (DCGI) and the Central Drugs Standard Control Organization (CDSCO), the Indian regulatory authority, introduced a two track process allowing rapid approval of clinical trials that were part of a global development program.

So we’re all set, right? Sadly, the reality and the promise have not quite met. The DCGI’s office underwent a change at the top shortly after the new approval process was put in place and clinical trial approvals languished for months, against published expectations of 90 days. Despite having well placed regulatory liaisons in New Delhi, CROs can obtain little information to give sponsors, who in turn became disillusioned with the process once again, even with the enticing prospect of all those treatment-naive patients and proven rapid enrollment rates once the trial eventually started.

India flag

Harmonization of Indian Regulatory Process

Into this rather frustrating situation has come reason to hope. Recently the CDSCO has signaled an interest in providing more transparency and greater accountability among all parties by releasing several new guidances that harmonize Indian regulatory processes with other clinical trial countries. First, Schedule Y-1 (the Indian counterpart to Title 21 of the Code of Federal Regulations) was amended to require all CROs working in India to register with the authorities to conduct clinical trials (scroll down in the link for English). This requirement has rather more teeth than the FDA’s move in 2009 to require IRB registration, as the authority can reject a CRO’s application.

Secondly, CDSCO this summer published a draft guidance to clarify and streamline the process for obtaining permission to import drugs in small quantities, fewer than 100 doses per patient, for use in clinical trials. This will differentiate from the large quantity application process already in place. Should this draft become a final rule, it would encourage sponsors and CROs to be more precise with their drug calculations on the import license, and to make contingency plans should they wish to expand an existing trial. Despite this apparent additional hurdle, the draft is intended to provide for more uniformity of decision making by the reviewers, and is not expected to change operational policies CROs already have in place.

Finally, CDSCO issued a final guidance on clinical trial inspection procedures effective November 2010, a kind of bioresearch monitoring manual. As with the small quantity test license draft, this guidance provides clear expectations for inspectors and sponsors in preparing for, conducting and reporting an inspection at a clinical trial site or a CRO/sponsor facility, as well as follow up and response actions.

clinical trial

Quest for Quality
Clinical Trial Data

Taken together with the recent introduction of an Indian clinical trials registry listing all clinical trials and sites in India, these changes though incremental, signal CDSCO’s desire to improve oversight of clinical trials and provide clarity for the sponsors and CROs who conduct them. There is even a glimmer of hope that the clinical trial approval process itself might be addressed soon, as October will see a change to the DCGI, India’s top drug official who ultimately approves all applications. Reasonable, reliable approval intervals combined with all the other attractive clinical trial attributes and recent improvements, India is truly an important solution in the quest for high quality clinical data.

Jacquie Mardell
Anhvita BioPharma Consulting, Inc. (Pvt Ltd)

Please Leave a Comment to Contact Jacquie

Central Drugs Standard Control Organization

India GCP & Clinical Trial Inspection Guidance Documents

Clinical Trials Registry – India


Please take a short 3-question survey to help GxP Perspectives improve! Survey begins 22 SEP 2011


A comment worth reading from Anusha Reddy Mirayala: “In addition to the above mentioned changes made in Indian clinical trial process.I would like adding the following points

The ministry of health & family welfare, India has constituted a 12 new dug advisory committees to assist the DCGI in the matters related to review and regulatory approval of new drugs and clinical trials (except INDs), chalking a roadmap for proper development of new drugs.

Also the agency has come up with the draft guidance on approval of clinical trials and new drugs in july this year. which will help the industry to submit the required documents in a more realistic manner and also eases the agency review process in a systematic way.”


Article from Healthcare Management in India by Dr. Arun Bhatt, From guidelines to law

Article from Bio Spectrum on New DCGI expected to takeover in November

Thanks to our readers in India!


On the Blogroll: Compliance Zen discusses Building Compliance in India

Rebar Interactive has 22 great GCP websites, and more.


Tufts Center for the Study of Drug Development: Article on Protocol Amendments: One third can be avoided.

Drug shortage at hospitals could be deadly, by Linda A. Johnson, The Associated Press


You can help out GxP Perspectives! Please let your colleagues and friends know about GxP Perspectives and the discussion on risk-based monitoring. I also encourage you to get an email subscription (on the sidebar to your right) or join the GxP Perspectives LinkedIn Group (below).


Training Opportunities:

training GxP

Audits & Risk Management

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.

GxP Audit & Risk Management Brochure


FDA Clinical Investigator Course,
7-9 November 2011, Silver Springs, MD


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.

GxP Perspectives LinkedIn Group

GxP Perspectives on twitter: @GxPPerspectives

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FDA Releases Draft Guidance for Monitoring Clinical Trials

September 4, 2011

FDA releases draft guidance document for monitoring clinical trials

FDA Draft Guidance Offers New Methods of Monitoring Clinical Trials

At long last, FDA has released a new draft guidance document for monitoring clinical trials. The previous FDA guidance document, Guideline for Monitoring Clinical Investigations (1988/1998) was withdrawn earlier this year. The new draft guidance document, FDA Guidance for Industry- Oversight of Clinical Investigations– A Risk-Based Approach (August 2011), discusses the changes in the way clinical trials are conducted and new methods of monitoring clinical trials. There is a 90-day comment period where members of industry, professional organizations, and the public can submit written commments to the agency for review and consideration.

In this Guest Commentary veteran monitoring specialist Lorraine Ellis gives her perspective on the new draft guidance for monitoring clinical trials.

Guest Commentary by Lorraine D. Ellis, MS, MBA

When I started monitoring, the Investigators completed CRFs from the source documents and there were few Clinical Research Coordinators (CRCs). Usually an office nurse or staff member would complete the forms when they had “free” time. Three decades later, sites, studies, and monitoring have changed significantly. Investigator sites must have significant study infrastructure (SOPs and facilities, etc) and trained/experienced staff to complete the complex trials of the 21st century. So it is significant that the 1988 Guidance document has been retired and the new guidance on monitoring describes FDA’s view on applying 21st century technology and methods to monitoring.

There are several key advances in this guidance. The guidance describes the term “centralized monitoring” for the many practices of using technology to review data off-site. This term and other FDA comments describe using “off-site” monitoring as one of the acceptable methods of monitoring data quality and study conduct. This guidance will intensify the discussions of “why do we need monitoring every 4 to 6 weeks with 100% source document verification” and “what is the best monitoring procedure for this study”. Also, FDA outlines more detailed monitoring plans as the risk based approach requires that monitoring approaches should be tailored to the trial.

clinical trial monitoring fda guidance document

Poorly Designed Protocols, CRFs, or Trial Instructions

FDA suggests a multi-factor approach to ensure data integrity, compliance and patient protection since there are many trial factors that can affect these trial elements besides monitoring. For example, poorly designed protocols, CRFs, or trial instructions could cause fatal trial errors despite extensive monitoring. Inadequate, incomplete or poor training of all involved in the trial, Investigators, staff, monitors etc., could also decrease study quality. The guidance encourages using various methods of study conduct review to assess these study elements as well as data quality.

The second half of the guidance provides information on monitoring plans and their expected content. Currently monitoring plan content and quality vary among Sponsors so this detailed section should increase monitoring plan quality and detail as it describes methods appropriate to the study. Since this guidance promotes custom monitoring plans based on variables of the study such as scope and complexity, these sections will assist Sponsors in designing and implementing those monitoring practices appropriate to the study.

FDA clinical trials guidance

"Greater Reliance on Centralized Monitoring"

One sentence will probably be surprising to some veteran monitors and Sponsors. “FDA encourages greater reliance on centralized monitoring practices than has been the case historically, with correspondingly less emphasis on on-site monitoring”. Many Sponsors that have instituted EDC and other technologies for data collection/review, have not decreased on-site monitoring time they continue to rely on the “gold standard” of visits every 4 to 6 weeks and 100% SDV. FDA does advise that at least one on-site monitoring visit should be done to ensure processes and procedures are in place at the site to ensure data quality. FDA continues that to use centralized monitoring properly, Sponsors need to develop methods and standard operating procedures so that site records, data entry, and data reporting follow well-defined procedures.

FDA guidance on clinical trials monitoring

Risk-Based Approach

FDA recommends that the monitoring plan is developed based on a risk assessment of the study complexity, study endpoints, disease complexity, geography, Investigator experience, EDC capabilities, Investigational product safety, study stage and quantity of data. After risk assessment, the Sponsor prepares a tailored monitoring plan for each study that will address that risk and outlines the multi-faceted approach to the trial. The plan, that includes monitoring procedures, monitoring responsibilities, and trial requirements, should be in sufficient detail so monitors and others involved can carry out their respective tasks correctly.

The plan should also include: monitoring methods, communication of monitoring findings, resolution of issues, training topics, training evaluation, and monitoring plan amendments.
It will be interesting to read the comments sent to FDA in the next 90 days. Some Sponsors will say “it’s about time” monitoring will be optimizing 21st century technology. Others may struggle with the changing of the “gold standard” of monitoring. In any case, this guidance may be the catalyst the industry needs to optimize monitoring methods and effectiveness.

FDA Guidance for Industry: Oversight of Clinical Investigations– A Risk-Based Approach

Visit Lorraine’s Website


How to comment: 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

The Federal Register Docket Number is FDA-2011-D-0597


You can help out GxP Perspectives! Please let your colleagues and friends know about GxP Perspectives and the discussion on risk-based monitoring. I also encourage you to get an email subscription (on the sidebar to your right) or join the LinkedIn group (below).

Please take a short 3-question survey to help GxP Perspectives improve! Survey begins 22 SEP 2011

On the Blogroll: Chromosome which features an excellent post on, “The Site’s Side,” by Jae Chung, founder of goBalto, Inc., located in San Francisco. The post discusses some of the problems clinical sites face with monitors.

On The Blogroll: On Biostatistics and Clinical Trials– Finally a blog on biostatistics that I can almost read:) It is written by Dr. Deng, 邓春勤 A Medical Doctor turned into Biostatistician in Clinical Trial and Drug Development Industry
clinical trials FDA monitoring guidanceThere have been some great comments on the GxP Perspectives LinkedIn group on the draft guidance document. There is also a new logo for your viewing pleasure. I invite everyone to join the GxP Perspectives LinkedIn Group and join the discussion.

GxP Perspectives LinkedIn Group

The FDA, Center for Drug Evaluation and Research (CDER) is announcing an industry workshop entitled ‘‘CDER Small Business Assistance – Clinical Trials and Electronic Submissions.” This two day event will be held in two California locations consecutively. The first workshop will be held in Los Angeles, CA, on September 26-27, 2011, followed by a second in San Francisco, CA, on September 28-29, 2011.
This just in: Request for Comments- Exculpatory Language Used in Informed Consent, a joint FDA and OHRP draft guidance document (September 2011)
GxP Perspectives has returned to twitter: @GxPPerspectives

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FDA Proposes User Fees for Biosimilar Products

May 22, 2011

FDA biosimilar user fees

FDA Proposal on Biosimilars

Biosimilars or “add-on biologics” have been making the news of late. These are replacements for patented biological drugs developed by biotechnology companies like Genentech and Amgen. Are they the same as generic drugs? No, large molecule biologics products are far more complex than a tablet of aspirin. They can’t be exactly reproduced in the manner of a generic drug which is why they are called, “biosimilars.” How can they be regulated by FDA? That’s a good question that veteran consultant Michael Hamrell discusses in this Guest Commentary. It is a complex and difficult issue and Hamrell does an excellent job of explaining FDA’s Proposal.

User Fees for Biosimilars

FDA Biosimilars User Fees

Differences in Large Molecule Products

The FDA recently issued it proposed plan for user fees for the new biosimilar products that were authorized under the Healthcare Reform Act in the subsection on Biologics Price Competition and Innovation Act of 2009. This law added a new section (351(k)) to the Public Health Service Act that gives the FDA the authority to approved product biosimilar and interchangeable with a licensed reference biological product. As part of the implementation of the law and regulations for the development of these biosimilar products, the FDA is preparing a proposal for how user fees will be assessed and collected for these products. These fees are proposed to begin with the next reauthorization of the User fee program in FY2013 (October 1, 2012).

Under the initial plan, the user fees for the new biosimilar products will overall be the same as for new biological products. Since FDA expects that marketing application review, preapproval facility inspections, and safety issues will be comparable for 351(k) and 351(a) applications, for the initial 5-year authorization, the Agency proposes to maintain the same PDUFA fee levels for 351(k) marketing applications, manufacturing establishments, and products. However, the Agency proposes to modify this structure to provide resources in the near-term because, as noted in section I of this document, there is no existing inventory of marketed products that would generate fees.

biosimilar FDA user fees

Differences in the Biosimilar Pathway

One key difference is the planned inclusion of a Biosimilar Product Development Fee, a part of the user fee to be paid upon submission of the IND and annually thereafter while the molecule is under active development that is intended for a single 351(k) application. The initial product development fee is estimated to be around $150,000 per year. Failure to pay the development fee on initial IND submission or annually as required would result in the IND being placed on Full Clinical Hold. The other difference is when the applicant submits the associated 351(k) marketing application, the sum of the previously paid annual Biosimilar Product Development fees would be deducted from the 351(k) marketing application fee.

This is a major difference, at least initially from drug development under the NDA regulations, where no user fee or partial fee is paid during the development phase. The only user fee is paid upon submission of a marketing application. Since the development fee is payable annually during active development, it will be critical that the development program proceed in a logical and efficient manner. Delays in clinical trials, due to GCP problems or other issues will now cost money by extending the IND development phase and having to pay another annual IND development fee.

FDA Biosimilars

FDA is Seeking Input on Biosimilars

This is still a proposal at this point and the FDA is seeking input and comment on the proposal in order to move forward to finalize a plan. Anyone interested in commenting on the proposal should review the requirement for submitting comments contained in the Federal Register notice regarding the plan (76 FR 27062-27067).

Guest Commentary – Michael Hamrell


On the Blogroll: RegBlog on all things regulatory from the University of Pennsylvania Law School. Covers much more than FDA


=== Read more on biosimilars:

The Economist on Biosimilars

Read from Genentech on Biosimilars


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FDA & EU Requirements for Documentation & Approval of GMP Procedures

April 23, 2011

FDA documentation requirements

FDA Requirements for Signatures & Documentation

What does the FDA require for the documentation, signature, and approval of standard operating procedures (SOPs)? Are the requirements the same for Good Manufacturing Practice (GMP), Good Laboratory Practice (GLP), and Good Clinical Practice (GCP)? As it turns out, the answer is no. FDA has different regulatory requirements for GCP, GMP, and GLP regulations. In this Guest Commentary Kathie Clark describes the FDA and EU requirements for documentation and approval of GMP procedures. And understanding the basics of good documentation helps in any area of FDA regulated industry.

Guest Commentary:

Approval & Signature Requirements for GMP Documents, by Kathie Clark

Complete, accurate and clear documentation is key to maintaining compliance in a Good Manufacturing Practices (GMP) environment. Documentation is needed to define quality management principles, describe specific procedures, and maintain records that demonstrate that procedures were followed. Together, these directives, procedures and records demonstrate that a manufacturer is operating in a state of control, defined as “A condition in which the set of controls consistently provides assurance of continued process performance and product quality” .
GMPs specifically require that “The quality control unit shall have the responsibility for approving or rejecting all procedures or specifications impacting on the identity, strength, quality, and purity of the drug product.” But what does this mean in terms of required signatures?

Some people may be surprised to find that the US GMPs only require signature (or initials) for a handful of documents. The following are the specific GMP signature requirements:

FDA documentation GMP signature

What Procedures are Required?

§ 211.182 Equipment cleaning and use log. The persons performing and double-checking the cleaning and maintenance (or, if the cleaning and maintenance is performed using automated equipment under § 211.68, just the person verifying the cleaning and maintenance done by the automated equipment) shall date and sign or initial the log indicating that the work was performed.

§ 211.186(a) Master production and control records. …master production and control records for each drug product, including each batch size thereof, shall be prepared, dated, and signed (full signature, handwritten) by one person and independently checked, dated, and signed by a second person.

§ 211.186(b)(8) Master production and control records. A description of the drug product containers, closures, and packaging materials, including a specimen or copy of each label and all other labeling signed and dated by the person or persons responsible for approval of such labeling.

§ 211.194(a) Laboratory records. The initials or signature of the person who performs each test and the date(s) the tests were performed. The initials or signature of a second person showing that the original records have been reviewed for accuracy, completeness, and compliance with established standards.

§211.188(a) Batch production and control records. An accurate reproduction of the appropriate master production or control record, checked for accuracy, dated, and signed

documentation and signatures for FDA requirements

Review and Approval Process for GMPs

What’s the impact? Although some documents require signature according to regulations (CFR) in the US, a closer read indicates that the real emphasis is on defining and following a sound review and approval process, and being able to provide evidence of this, for all documents. There is no indication that you are out of compliance if an SOP or specification does not display handwritten or electronic signatures, as long as a valid process was followed for the document.

In Europe, GMPs would initially seem to set the bar higher as they state that “Documents containing instructions should be approved, signed and dated by appropriate and authorised persons.” However, a closer look at recent revisions made to EudraLex, The Rules Governing Medicinal Products in the European Union Volume 4, to support electronic signatures for GMP indicates that electronic signature requirements in Europe (for GMP documents) are less stringent that in the US:

Electronic records may be signed electronically. Electronic signatures are expected to:

a. have the same impact as hand-written signatures within the boundaries of the company,
b. be permanently linked to their respective record,
c. include the time and date that they were applied.

documentation and approval for FDA

Documentation for
Review, Approval,
& Release

Since there is no explicit requirement for the signature to appear in the document, this could be interpreted as an electronic approval recorded in a document management system. In summary, recommendations based on a review of the guidance include:

• Ensuring that the process to review, approve and release any GMP document is clearly defined in writing and followed consistently.
• Reviewing the signature requirements in the region in which you operate and determine the most efficient way to meet them.
• If you are not already using an electronic system to manage your documentation, considering the return on investment you may be able to achieve from cost reductions in the “Four Ps” of paper, printing, postage, and processing. If you must print, courier and archive paper documents to comply with the regulations, the cost can be significant.

Kathie Clark is Director, Product Management at NextDocs Corporation, where she is responsible for NextDocs’ Quality Management and Regulatory SharePoint-based document management solutions.


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PHARMACEUTICAL QUALITY SYSTEM Q10, International Conference On Harmonisation Of Technical Requirements For Registration Of Pharmaceuticals For Human Use, 4 June 2008

21 CFR 212.22 Responsibilities of quality control unit

EudraLex The Rules Governing Medicinal Products in the European Union Volume 4, Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Chapter 4: Documentation, Revision January 2011

EudraLex The Rules Governing Medicinal Products in the European Union Volume 4, Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Annex 11: Computerised Systems, Revision January 2011


On the Blogroll: The AssurX Blog recently posted this interesting article about FDA Inspections

Barry A. Friedman discusses FDA Warning Letters for APIs in China and clinical trial materials in the U.S..


FDA EU documentation

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SOPs in Europe: Required for GCPs?

April 1, 2011

SOP Europe requirements

SOPs for Clinical Trials in Europe

What are the differences in SOPs for clinical trials in Europe and the United States? Despite the fact that FDA and the European Medicines Agency are increasing their cooperation and collaboration there are still some formidable obstacles. One is the difference in regulations. The other is how much influence ICH E6: Good Clinical Practice: Consolidated Guidance has in different parts of the world. Today we have a Guest Commentary from The SOP Doctor, Dr Marie McKenzie Mills MICR, CSci, CBiol, MSB, a clinical scientist and trainer from the United Kingdom. She is here to give us a European perspective on SOPs. In 1996, Marie established McKenzie Mills Partnership (MMP), providing consultancy services including training, medical information, medical writing, and clinical research.

I will be publishing a post in Marie’s blog this weekend. Trans-Atlantic Cooperation!

Also: Please take the survey at the bottom of the post!

Guest Commentary

Is there a legal requirement to have SOPs for GCP in Europe?

by Dr Marie McKenzie Mills MICR, CSci, CBiol, MSB

Back in January, in his post “reflecting on the TMF”, Carl mentioned that the ICH Topic E6 Guideline for GCP may not appear to receive the same emphasis from some regulatory authorities as in the past. His post raised a flag about whether there’s a GCP standard other than ICH E6 GCP, which got me thinking. In Europe, a similar concern often pops up along the lines of: which GCP should we be following? So here goes with my answer, particularly for those of us affected by European legislation, with a wee bit of context to explain it.

In Europe, ICH GCP was adopted in July 1996, and became operational in January 1997. Despite having no uniform legal framework for implementation, it was largely adhered to within the European Community (EC) as a set of 13 internationally recognised principles for conducting clinical trials, founded in the bioethical principles that were established in the Declaration of Helsinki. But, its adoption as a regulatory standard was neither complete nor uniform.

SOP Europe

Does the Clinical Trials Directive Require SOPs?

In 2001, Directive 2001/20/EC – legislation known as the Clinical Trials Directive – eventually provided a common legal framework across Member States for monitoring and enforcing GCP standards applicable to clinical research implementation. However, Directives have to be transposed into national law, in each Member State (within three years of their publication). This created scope for differing interpretations of the intended regulatory requirements, somewhat at odds with the goal of harmonisation. Even so, ICH GCP is the cornerstone standard within both the Clinical Trial Directive (Article 1 (3)), and the GCP Directive (Directive 2005/28/EC: Introduction, points 1 and 8; Chapter 1, Article 1 (1a)). So, far from receiving less emphasis, its principles have been adopted in both Directives, where it provides a basic standard for the conduct of clinical trials in a “set of internationally recognised ethical and scientific quality requirements, which must be observed for designing, recording and reporting trials that involve the participation of human subjects”.

This then brings me to the question about requirements for SOPs. Even if this requirement isn’t explicitly stated in European legislation, the burden to satisfy it exists nonetheless, particularly for sponsors because, according to ICH GCP 5.1.1, they’re responsible for “QA and QC systems with written SOPs to ensure that trials are conducted in compliance with the protocol, GCP, and the applicable regulatory requirement(s)”. Likewise, IRBs or IECs – as they’re better known across Europe – also need to have SOPs for their functions (ICH GCP 3.2.2).

Europe SOPs require?

Requirements for EU
Member States

As it turns out, in the GCP Directive, the requirement for SOPs is emphasised less for sponsors, and more for Member States, since their inspectors need appropriate tools for verifying GCP compliance (Chapter 6, Inspection Procedures, Article 26: “Member States shall establish the relevant procedures for verification of good clinical practice compliance. The procedures shall include the modalities for examining both the study management procedures and the conditions under which clinical trials are planned, performed, monitored and recorded, as well as follow-up measures”.

So there you have it: SOPs are required tools for sponsors to ensure GCP compliance; and, for inspectors they’re required tools for verifying compliance. As an all-encompassing requirement in the GCP Directive it often seems to escape everyone’s notice, perhaps because it appears understated. But, it’s there in Chapter 2, entitled Good Clinical Practice for the design, conduct, recording and reporting of clinical trials in Section 1, Article 2 (4): “The necessary procedures to secure the quality of every aspect of the trials shall be complied with.” I don’t know about you, but I think that’s all about SOPs. What do you think?

Links to the Clinical Trials Directive, GCP Directive and the ICH GCP guideline can all be found on the European Medicines Agency website on the link below.

European Medicines Agency (EMA)

EMA GCP Inspections

Marie’s Blog on the Difference between ICH and WHO GCPs

Carl’s Guest Post on Marie’s Blog on Differences Between FDA & EMA Sponsor/CRO Requirements


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On the Blogroll: New from the UK: Assero UK
“Working to connect your data…”

And, an interesting development:

PharmTech Talk on EU Transparency Initiative


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There are some important new FDA Warning Letters:

Warning Letter on Fraud at Clinical Site

Warning Letter for GMPs at Clinical Supplies Facility

Which brings us to a new feature from FDAzilla on FDA 483s

Read the Press Release on 483s

For more information about Europe you can read:

Applied Clinical Trials, View From Brussels by Peter O’Donnell
Jobs in Clinical Research? The April issue of the Journal of Clinical Research Best Practices just arrived on my doorstep (actually my email inbox) with a review by editor Norm Goldfarb on a new book, “Careers Opportunities in Clinical Drug Research” by Rebecca J. Anderson. At $59.00 it is a bit pricey but reading Norm’s journal always gives you a spectrum of information on clinical trials. You should consider an introductory Free Subscription to the Journal.

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