eCTD as a Required Format for FDA Submissions

October 29, 2011

eCTD Pyramid

The eCTD Pyramid

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

Five Steps to Become eCTD Ready, by Kathie Clark

In FDA’s PDUFA V Commitment Letter 8-31-2011, the agency announced their intention of issuing draft guidance for required electronic submissions in eCTD format by December 31, 2012, with final guidance no more than 12 months after the close of the public comment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

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

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

eCTD

Get Educated on eCTD

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

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

eCTD

The Decision to Outsource

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

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

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

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

(eCTD pyramid graphic- Wikipedia)

By Kathie Clark

Kathie’s Website: NextDocs

Ask Cato Blog

The eCTD Summit

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

Location of Monitoring guidance FR

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

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


An Ethical Question on Medical Oncology Research

October 25, 2011

oncology question

An Ethical Question on Clinical Trials

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

An Ethical Question on Medical Oncology Research:

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

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

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

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

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

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

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

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

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

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Please leave a comment on this question. Thanks!
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There are THREE Weeks left to comment on the Draft FDA Guidance Document on Risk-based Monitoring
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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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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You can help out GxP Perspectives! Please let your colleagues and friends know about GxP Perspectives. I also encourage you to get an email subscription (on the sidebar to your right) or join the GxP Perspectives LinkedIn Group (below).

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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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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)

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

GxP Perspectives LinkedIn Group

GxP Perspectives on twitter: @GxPPerspectives

Follow GxPPerspectives on Twitter
====
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.


Informed Consent & Research Ethics Discussed at WIRB Annual Training Seminar

October 2, 2011

Seminar on Informed Consent and Research Ethics

WIRB Training Seminar was Held in Seattle, WA

“Obtaining consent does not make an unethical study ethical,” Dr. Marjorie Speers told the Annual Training Seminar of the Western Institutional Review Board (WIRB). Speers is the President and CEO of AAHRPP (Association for the Accreditation of Human Research Protection Program). She pointed out that, although many IRBs focus on the informed consent process, protocol design is an equally important ethical consideration. The focus of this year’s seminar was informed consent and the speakers’ presentations led to some lively discussion on consent forms, protocol design, research in the developing world, and financial disclosure.

The seminar, which WIRB opens to research professionals in the Puget Sound, features national experts on bioethics and the regulation of IRBs. Among the speakers were Dr. Speers; Dr. Jerry Menikoff, Director of the Office of Human Research Protections (OHRP); Dr. Vincent Ahonkhai, Senior Regulatory Office, Bill and Melinda Gates Foundation; and, Dr. Jeremy Sugarman, Professor of Bioethics and Medicine, Johns Hopkins University. The University of Washington and the Fred Hutchinson Cancer Research Center co-sponsored the seminar with WIRB.

informed consent and research ethics

Simplifying the Informed Consent Process

A recurring theme was the need to shorten consent forms to make them more accessible to research subjects. Dr. Speers referred to most of the required elements of informed consent a “required disclosures,” stating that “disclosures” was a preferrable term. During discussion periods there were several comments that the disclosures had more to do with legal concerns than with involving the research subject in an informed consent process. Dr. Speers stressed that, “too much information is no information.”

Dr. Speers spoke of the need to involve communities as well as the individual research participants. “Communities can be harmed and benefitted by the research,” maintained Speers. “Generally, the public does not understand the drug development process,” Speers said, the aim of gaining new knowledge.

The seminar discussed some humorous examples of researchers not understanding sensibilities in the developing world. For example, informed consent forms frequently use units of measure such as a teaspoon or quarter cup of blood taken for laboratory analysis. However, when the research was in sub-Saharan Africa, because researchers were using units of measurement most common in cooking, potential subjects assumed that the blood was going to be cooked, not analyzed. This led to worries about witchcraft, which was clearly not the intent of the researchers.

WIRB invited a research participant, Debbbie, to address the seminar. Debbie had participated in many cystic fibrosis studies in the past 20 years. She talked about how access to healthcare and money were her primary motivations for participating in a clinical trial. She had lost her health insurance a few months before enrolling in the study. Then she developed pneumonia. During the run-in phase of the study there was a “cleanout” using antibiotics, a common practice in CF studies. Participating in the clinical trial directly benefitted her healthcare. One of the reasons she enjoyed research participation was the access to healthcare and cutting edge developments in the treatment of cystic fibrosis.

The Influence of Money on Research Ethics

Money was a major topic of conversation, as always at a meeting discussing bioethics. Debbie was asked, “how much of a factor is it?” Quite a lot, she replied. Speakers discussed the question from the perspective of financial disclosure. Dr. Speers said that any financial interest by a member of the research team should be an expected disclosure. Others pointed out that the only type of financial relationship that significantly affected potential research participants was when the researchers had an equity interest in the research drug. But not always in ways you might expect. One potential subject said that when learning the PI owned stock in the company sponsoring the research, they thought, “the drug must work,” and wanted to participate.

There was one embarrassing moment for quality assurance professionals during a talk by Dr. Maria Greenwald, a researcher from California. She had recently been audited by a sponsor QA auditor who cited her for failing to report “protocol violations” to the IRB. The protocol required periodic laboratory tests for calcium levels, which were a concern for the investigational product.

Research Ethics and Audit Findings on Calcium Levels

Elevated Calcium Levels

When blood tests revealed significantly increased calcium levels for one research subject, Dr. Greenwald ordered laboratory tests at every study visit, more frequently than the protocol required. She considered this necessary for patient safety using her medical judgment, as required by the Form FDA 1572. The auditor disagreed and insisted that she had violated the protocol.

I remember my own inspection training in the FDA Bioresearch Monitoring program. “Never argue the practice of medicine with an MD,” I was told. When Dr. Greenwald said that she ordered the lab tests for patient safety according to her medical judgment, the auditor should have accepted it and merely noted it in her report.

The public seminar concluded with David Forster, the Chief Compliance Officer for WIRB pointing out a three-page informed consent form approved by WIRB during the first year of its existence. It had all of the required elements, or disclosures, and was simple and to the point. He challenged WIRB board members to see if it was possible to return to a clear, simple consent form. Most appeared up to the challenge.

Carl Anderson
GxP Perspectives
02 October 2011

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Good Documentation Practice: Thanks to Jerry Chapman at IPQ Publications for this useful resource list for GDP Guidance Canon

Information about IPQ Publications

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Next Week: Veteran GCP educator, David Montgomery opines on the
FDA Draft Guidance on Risk-Based Monitoring

Six Weeks Left to Comment on Risk-Based 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

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

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Just released– FDA Draft Guidance for Medical Devices: De Novo Classification Process (Evaluation of Automatic Class III Designation)
Read the Federal Register Announcement

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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).

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

Follow GxP Perspectives on twitter: @GxPPerspectives

Follow GxPPerspectives on Twitter

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Pacific Regional Chapter SQA Fall Training 10-11 November at Allergan in Irvine, CA. The training will feature a debate which should be an interesting development in training workshops: Debi Garvin, MS, RQAP-GLP and Paula Parsons: Debate: The role of CAPA in a GLP environment.

PRCSQA Fall Training


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