FDA Issues Draft Guidance on Medical Device Clinical Trials

August 15, 2011

FDA clinical trial medical device

FDA Seeks Comment on Draft Guidance Document

FDA has issued two new draft guidance documents on medical device clinical trials to support a Pre-Market Approval application (PMA). Approximately 30% of FDA regulated clinical trials are for medical devices and are regulated by the IDE regulations (21 CFR 812). The remaining 70% are for drugs and biologics and are regulated by the IND regulations (21 CFR 312). The majority of guidance documents, including ICH E6 for good clinical practice, and the majority of clinical trial vendors address drug products, not medical devices. Although Good Clinical Practice is relevant to all clinical trials there are unique aspects for device studies as opposed to drug studies. This is one reason that FDA issued a device-specific guidance document.

The draft guidance document, Draft Guidance for Industry, Clinical Investigators, and Food and Drug Administration Staff – Design Considerations for Pivotal Clinical Investigations for Medical Devices (August 15, 2011), addresses therapeutic and aesthetic devices and diagnostic devices. Areas the document address include; Regulatory Framework for Level of Evidence and Study Design, The Importance of Exploratory Studies in Pivotal Study Design, Clinical Outcome Studies, Diagnostic Clinical Performance Studies, and Sustaining the Level of Evidence of Clinical Studies. The guidance states that its scope is:

clinical trials FDA medical device

Design Considerations for Pivotal Studies

“This guidance describes principles that should be followed for the design of premarket clinical studies1 that are pivotal in establishing the safety and effectiveness of a medical device. Practical issues and pitfalls in pivotal clinical study design are discussed, along with their effects on the conclusions that can be drawn from the studies concerning safety and effectiveness.”

The Agency also released the draft guidance document; Draft Guidance for Industry and Food and Drug Administration Staff – Factors to Consider when Making Benefit-Risk Determinations in Medical Device Premarket Review (August 15, 2011). The Agency states:

FDA clinical trial medical device

Benefit-Risk Determination

“This guidance document explains the factors that FDA considers when making benefit-risk determinations in the premarket review of certain medical devices. The processes discussed in this guidance are applicable to devices subject to premarket approval (PMA) applications and, in limited cases, devices subject to premarket notification (510(k)) requirements. This guidance applies to both diagnostic devices and therapeutic devices.

Although guidance is not binding, the concepts and factors described herein generally capture how benefit-risk determinations are made by FDA during the premarket review process.”

Read the Guidance Document on Design Considerations

Read the Guidance Document on Benefit/Risk Determinations


ALSO of interest: FDA is currently accepting comments on the IVD Draft Guidance Document on In Vitro Companion Diagnostic Devices.

The draft guidance was issued 14 July, Bastille Day. I wish that I could explain it to you as well as Jamie K. Wolszon at the FDA Law Blog, but I can’t so I recommend taking a look over there:


FDA Law Blog on IVD Companion Devices


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Required Summer Reading: Essex IRB Warning Letter. Earlier this year FDA warned of a fictitious submission to central IRBs. Essex took the bait and approved the fictitious submission.


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


FDA warning letter

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FDA Clinical Trials: Quality Considerations for Pivotal Studies

April 9, 2011

clinical trials considerations pivotal

When Should Quality Begin?

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

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

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

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

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

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

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

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

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

clinical trial consideration pivotal

QA for the Data Lifecycle

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

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

pivotal clinical trial

Increased Enforcement of
Part 11

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

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

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

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

pivotal considerations for phase III clinical trials

QA Audits of Clinical Sites

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

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

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

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

Pivotal clinical trial considerations

Conduct Regular GCP Training

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

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

Sponsor audits and mock FDA inspections

pivotl phase III clinical trials

Always Prepare for an FDA Inspection

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

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


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

Society for Clinical Data Management

ICH Guidance Documents
On the Blogroll: PharmTech Talk has had a number of interesting blog posts of late.

FDA clinical trials pivotal studies

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New FDA Guidance Documents Planned for 2011

January 9, 2011

FDA Guidance Documents 2011

FDA Plans New Guidance Documents in 2011

FDA just issued a new draft guidance document for Electronic Source Documents in Clinical Investigations (see below) and has more in the works. In this Guest Commentary, John Avellanet, founder of Cerulean Associates LLC, takes a look at what is in store for 2011 as far as FDA Guidance Documents with a focus on new documents for postmarket surveillance. The article is excerpted from a lengthier article in John’s newsletter SmarterCompliance. John forecasts new guidance documents every year in his newsletter. There is a link to John’s website below.

Guest Commentary by John Avellanet:

FDA postmarket surveillance is the emphasis of at least six different guidance documents planned for publication in 2011. And these are in addition to the new International Conference on Harmonization (ICH) and Global Harmonization Task Force (GHTF) documents expected, including a GHTF guidance on the handling of recalls and field safety corrective actions (see below).

The list of FDA postmarket surveillance guidance documents includes:

1. Chemistry, Manufacturing, and Controls (CMC) – Postmarketing Plan
2. CMC Postapproval Changes Reportable in an Annual Report
3. Pharmaceutical Manufacturing Statistics and Trend Analyses
4. Best Practices for Conducting Pharmacovigilence Studies Using Electronic Healthcare Data (remember that since FDAAA of 2007, the term “study” explicitly means postmarket nonclinical study)
5. Medical Device Reporting for Manufacturers
6. Postmarket Surveillance and the National Competent Authority Report Exchange Criteria and Report Form
7. Types of Submissions for Postapproval Changes to Combination Products

FDA Guidance Documents

Expect New REMS Guidance from FDA

I also expect the agency to release a revised risk evaluation and mitigation strategies (REMS) guidance, at least in draft form, by year’s end. Part of this release will be the creation of a pilot program to test what a standard REMS could like as a default part of any new drug or biologic submission. This means one more step toward pushing the industry to create some type of REMS for every single new drug or biologic developed. The agency will maintain an approach to a standard REMS that will be harmonized with other regulatory member agencies in the ICH. And while such a revised draft REMS guidance may come as a separate document, I suspect the agency may take a newer tact: “guidance by FAQ.”

guidance documents

EMA is Also Releasing New Guidance & Clarifications

Both the European Medicines Agency (EMA) and the UK’s health agency (MHRA) have begun publishing clarifications and revisions to guidance documents and regulatory interpretations using question and answer formats posted on agency webpages. The FDA adopted this approach most recently in its “guidance” (for Buildings and Facilities) on avoiding moldy or musty odors in drugs. Might the agency harness the “guidance by FAQ” approach for its upcoming standardized REMS draft and pilot?

The standard REMS template – while seeming to add more requirements to drug development – will actually provide manufacturers and developers more flexibility, something already known to readers of Get to Market Now! Turn FDA Compliance into a Competitive Edge. While I do not expect the REMS guidance and template to be finalized until after the pilot program is complete, consider developing a high-level REMS as part of any late stage development today. Expect to be able to talk intelligently to FDA reviewers of your plans for a postmarket surveillance program. A high-level draft REMS strategy (you need not share the actual document with the agency) will only help.

Finally, be aware that in 2011, the HHS Office of Inspector General (OIG) will examine the FDA’s postmarket surveillance activities, with a report expected to be published in 2012. This will inevitably result in more postmarket guidance, and may give the FDA the backing it needs to make a basic REMS part of any new drug or biologic submission by 2014.

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

Global Harmonization Task Force focuses on medical devices

International Conference on Harmonization focuses on drugs and biologics

SPECIAL ANNOUNCEMENT: From the FDA Alumni Association (FDAAA): The WHO is seeking a pharmaceutical technical officer to work in China ondrug policy. The position looks very interesting. Please forward to anyone you think might be interested. Please contact WHO directly if you have questions. For info contact <a href="Florence Houn “>Florence Houn at FDAA. or view the WHO AnnouncementWHO Announcement


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Special Notice: The Blog was published in the Journal of Diabetes Science & Technology on the topic of Supervisory Responsibilities of Investigators with my colleagues Ann Berenbaum and Patti Young.

Access the Abstract Here


FDA Warning Letters to International Companies for CAPAs & Complaints

November 28, 2010

FDA warning letter CAPA complaint

Warning Letters for CAPAs & Complaint Investigations

In the past 90 days FDA issued five Warning Letters to international firms for GMP failures to adequately investigate complaints. Whether it is GMPs, GCPs, or GLPs FDA is making the case that when things go wrong, it is a company’s responsibility to investigate and implement the necessary corrective and preventative action (CAPA), In the past, FDA was hesitant to issue Warning Letters to firms outside the United States. That clearly is changing as both the Center for Devices and Radiological Health (CDRH) and the Center for Drug Evaluation and Research (CDER) have issued Warning Letters to companies in Canada, Switzerland, China, Sweden, and India. Although the companies are from diverse locations and range from medical devices, active pharmaceutical ingredients (APIs), and finished pharmaceuticals, one issue connects them all: the failure to adequately address complaints. For the medical device Warning Letters, corrective and preventative actions (CAPAs) figured prominently.

FDA first opened international offices in 2008 in India and China and now has offices in Europe and Latin America as well. The international offices are predominantly focused on GMPs for food, drugs, and medical devices. FDA has also stepped up its inspections of clinical trials in international locations including Russia and Eastern Europe. However, there has not been the corresponding surge in Warning Letters. At least not yet. Here are charges that FDA made in the international Warning Letters:

CAPA complaint FDA warning letter

Failure to Investigate Bacterial Contamination

Claris (India): On April 15, 2010, your firm received a complaint from a U.S. distributor (Sagent Pharmaceuticals) informing you that Metronidazole Injection USP IV bags (lot A090744) were contaminated with a informing you that Metronidazole Injection USP IV bags (lot A090744) were contaminated with a swirling mass, which the complainant identified as the fungus Cladosporium species. There is no information in the Complaint Investigation Report to show that Claris initiated an investigation to determine the root cause and extent of the problem until April 26, 2010, when Claris received this contaminated large volume parenteral and examined it.

Storz Medical (Switzerland): Failure to establish and maintain adequate procedures for verifying or validating the corrective and preventive action to ensure that such action is effective and does not adversely affect the finished device, as required by 21 CFR 820.100(a)(4). For example, no protocol, including acceptance criteria, was established for the validation of Change Request (b)(4). Additionally, there was no documentation showing that this change was validated. The change was implemented to fix cracked cooling pumps in the Modulith SLX-F2.

The Warning Letter goes on to say:

international complaint investigation failure FDA

Failure to Establish Procedures for Complaints

Failure to establish and maintain adequate procedures to ensure that any complaint involving the possible failure of a device, labeling, or packaging to meet any of its specifications shall be reviewed, evaluated, and investigated unless such investigation has already been performed for a similar complaint and another investigation is not necessary, as required by 21 CFR 820.198(c).

Neoventa Medical AB (Sweden): 1. Failure to establish and maintain adequate procedures for implementing corrective and preventive action that include requirements for verifying or validating the corrective and preventive action to ensure that such action is effective and does not adversely affect the finished device and that all activities required under this section and their results be documented, as required by 21 CFR 820.100(a)(4) and (b).

2. Failure to establish and maintain adequate procedures for receiving, reviewing, and evaluating complaints by a formally designated unit, as required by 21 CFR 820.198(a).

Once again the direct connection between the failure to investigate complaints and the failure of a system of CAPA.

FDA Warning Letters CAPA

Chinese API Manufacturer Hit with FDA Warning Letter

Yunnan Hande (China): Failure to thoroughly investigate complaints for APIs batches that do not meet the United States Pharmacopeia (USP) compendial requirements that may have been associated with the specific failure or discrepancy. In addition, your investigation was not extended to other batches that may also be affected.

Pega Medical (Canada): Failure to establish and maintain the requirements, including quality requirements, that must be met by suppliers, contractors, and consultants, as required by 21 CFR 820.50(a)… For example, Complaint NCR No. (b)(4) reported…”

Read the Warning Letters:

Storz Medical, AG Warning Letter

Yunnan Hande Biotech Warning Letter

Claris India Warning Letter

Pega Medical Warning Letter

Neoventa Medical AB

FDA International Resident Posts

And What About Clinical Trials?

At a recent FDANews conference FDA representative Ann Meeker-O’Connell, M.S., Division of Scientific Investigations, Office of Compliance CDER/FDA, said,

FDA warning letter international complaint investigations

Clinical Trial CAPAs Face Different Challenges

“But, clinical trials are inherently variable systems with a goal of producing reliable data for regulatory decision-making . . . How can this be reconciled with a quality system framework originating in mass manufacturing?”

That is a very good question and one that many of us have been wrestling with. However, it is clear that FDA has been taking on the question of the international nature of the drug and device industry, including manufacturing and clinical trials.

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UPDATE: There is a very interesting Important Notice to IRBs that is on the FDA website. Sort of a Coast IRB redux.

Public Comment Period is Open for New FDA Draft Guidance:
FDA Draft Guidance on Electronic Source Data in Clinical Investigations


Visit the TMF Page at the Top Right of the Blog! I am trying to assemble resources for those of us concerned with the Trial Master File. I welcome any contributions you might have of interesting articles and resource documents.

On FDA’s Website there are Two New Warning Letters from FDA to Clinical Investigators that show the need to effectively respond to a Form FDA 483, Inspectional Observations, with a well thought out CAPA Plan.

FDA Guidance: FAQ for In Vitro Diagnostic Devices (IVDs)

September 27, 2010


FDA Guidance: FAQ for
In Vitro Diagnostic
Medical Devices

In Vitro Diagnostic medical devices (IVDs) have long occupied a poorly understood sector of clinical trials. Now, a recent FDA document, Guidance for Industry and FDA Staff: In Vitro Diagnostic (IVD) Device Studies- Frequently Asked Questions (June 25, 2010) clears up many questions. The FAQ offers resources including the definition of many basic IVD and medical device terms. Examples include the FDA definition of the difference between Invasive and Non-Invasive and the difference between a Significant Risk and Non-Significant medical device. The FAQ gives FDA contact information for IVD review divisions and the conduct of clinical trials. Most importantly, the FAQ discusses how IVDs meet the criteria for exemption from most requirements under medical device clinical trial regulations.

The FAQ discusses the requirements for the emergency use of investigational IVDs. It also discusses the differences in informed consent requirements between FDA and the U.S. Department of Health and Human Services which funds NIH studies. Frequently researchers think that if a study is exempt under DHHS regulations (Title 45 Part 46) that the study is exempt from FDA informed consent regulations found in 21 CFR Parts 50 and 56. FDA requires IRB and informed consent even if studies are exempt from most requirements of 21 Part 812.

The FAQ also discusses use of data collected from studies conducted outside the United States. The FAQ gives the following guidance:

… the PMA regulation, 21 CFR Part 814, allows foreign data to be used as the sole support of a marketing application but only if (1) the data are applicable to the U.S. population and to U.S. medical practices, including laboratory practices, (2) the studies have been performed by clinical investigators of recognized competence, and (3) the data may be considered valid without the need for an on-site FDA inspection or, if necessary, FDA can validate the data through an on-site inspection or other appropriate means (21 CFR 814.15(d)).

For IVD devices, FDA would consider differences in population demographics, disease prevalence, disease presentation, laboratory practices, and medical standards of care. If the sponsor plans to submit an application based solely on foreign data, FDA recommends that the sponsor consult with the reviewing division prior to submission of the application.


ICH Good Clinical Practice Can Also Apply to Medical Device Studies

The FAQ endorses ICH E6: Consolidated Guidance on Good Clinical Practice as a sound guidance document with sections applicable to medical devices as well as pharmaceuticals. It also discusses the draft ISO 14155 document:

Although the ICH document was written for studies of pharmaceuticals, sections of the guidance address study issues common to all investigational products. Thus, these sections of the ICH GCP provide a useful reference regarding the proper conduct of studies.

The draft ISO document specifically states that it does not apply to IVD devices. The draft ISO document is an international document intended to reflect basic practices appropriate to clinical trials worldwide. It does not include all of FDA’s specific requirements for clinical studies and is not presently a standard that FDA has officially recognized; therefore, we do not recommend that you rely on it.


Appendix 2 Shows Requirements for IRB Approval and Informed Consent

The FAQ has two charts, Appendix 1 and Appendix 2, that clear up decision making for IVD exeption criteria as well as informed consent requirements. And in keeping with current FDA clinical trial policy the FAQ emphasizes the use of quality systems for IVDs. The FAQ and two other relevant FDA guidance documents are below:

FAQs for In Vitro Diagnostic Devices

FDA Guidance on Informed Consent for IVDs Using Leftover Human Specimens

Comparison of FDA (21 CFR 50 & 56) and DHHS (45 CFR 46) Regulations

UPDATE: My favorite industry magazine, Applied Clinical Trials, now has a LinkedIn Group:
Applied Clinical Trials LinkedIn

++++In news from GxP Perspectives++++

Read the updated article on the Form FDA 1572 in:

Applied Clinical Trials “Closing Thought” on FDA 1572

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CAPA Basics- Corrective And Preventative Action

March 22, 2010

CAPA Basics

CAPA Basics

When developing a quality management program you need to discuss the basics of CAPA: corrective and preventative action, and how to come up with a CAPA plan that resolves the root causes of violations. In a guest commentary, veteran GxP consultant Barb Immel discusses CAPA basics. I first met Barb when she was teaching a 3-day drug development course at UC Extension and had invited me as a guest speaker. I sat through the entire three days and learned a lot.

Guest Commentary:

CAPA Basics By Barbara K. Immel

Poor corrective and preventive action (CAPA) and investigations continue to be among top FDA Form 483 deficiencies issued to drug, biologic, and medical device manufacturers. And FDA has been issuing warning letters citing inadequate corrective action to clinical investigators, institutional review boards, contract research organizations, and sponsors. It’s in everyone’s self interest to improve the quality of investigations and CAPA. The most important point to remember?

The depth and intensity of an investigation should match the potential risk to the patient.

1. Start with the requirements. Always follow all applicable regulations and standards, and go above and beyond the minimum requirements. Although the only organizations that are required to establish a CAPA system are medical device manufacturers, it has always been either a requirement or an expectation that all organizations in our industry will perform thorough investigations and implement effective CAPA. Helpful passages include, but are not limited, to:

Device CGMPs. Establishing a CAPA system is a CGMP requirement for medical device manufacturers producing product for the US (21 CFR 820.100).

Drug CGMPs. Conducting certain investigations and documenting and justifying deviations is required for manufacturers making product for the US. Inadequate investigations are a frequent CGMP deficiency (21 CFR 211.192).

CAPA laboratory

Good Laboratory Practice

Preclinical Requirements. Taking corrective action is required in the GLPs (21 CFR 58) for testing facility management (21 CFR 58.31), the study director (21 CFR 58.33), Clinical Requirements. And taking effective corrective action is implied in the GCPs. Relevant sections include but aren’t limited to the Responsibilities of Sponsors (21 CFR 812.40) and Responsibilities of Sponsors and Investigators (21 CFR 312 Subpart D).

2. Establish good surveillance. Carefully think about the data you need, and the speed with which you will require being notified. A surveillance system is only as good as the information it receives.

• Conduct thorough, frequent audits (most internal operations should be audited at least once a year, and critical suppliers should be audited frequently, such as once every 12-18 months). Ensure audits are done by experienced personnel, and that any identified issues are promptly addressed.

• Require that all employees immediately report to their supervisor when they deviate, make a mistake, or notice something unusual. Require that sites notify you rapidly of any issues or potential issues.

• Set up an effective trending system, to identify potential issues before they become a fire.

• Regardless of where you work in the industry, check out the following documents for ideas:

o AdvaMed Points to Consider When Preparing for an FDA Inspection under the QSIT Corrective and Preventive Action Subsystem:

o Global Harmonization Task Force Proposed Document: Quality Management System — Medical Devices — Guidance on corrective action and preventive action and related QMS processes:


Laboratory Requirements:

If you work with a laboratory, see FDA’s Guidance for Industry: Investigating Out-of-Specification Test Results for Pharmaceutical Production

• Ensure your system will allow you to notify FDA of any problems concerning your product or clinical trial within FDA required reporting timeframes (i.e., a field alert, medical device report, biologic product deviation report, adverse event or serious adverse event, etc.).

• Always include a link between your investigation and CAPA procedures and your FDA reporting procedures, including your recall procedure.


Review Recall Procedures

Any potential recall situation should immediately be brought to the attention of your QA executive. For recall SOP ideas, see FDA’s regulation (21 CFR 7) and FDA’s Guidance for Industry: Product Recalls, Including Removals and Corrections. Test your recall system at least once a year.

Remember: Each FDA District Office has a Recall Coordinator.


3. Create (or improve) your SOP(s) and systems. Every organization should have a failure investigation procedure that states the threshold for initiating an investigation. The decision whether to investigate should always be made by an experienced QA employee, and documented.

• Periodically ask employees or others using your system what’s driving them crazy about it, and act on the results.

• Make sure your system requires the early categorization or determination of risk, and the ability to rapidly escalate the importance of items. Your system should include how management will be routinely informed of ongoing investigations and CAPA activities, and how they will be immediately informed of critical issues.

4. Define your terms. For medical device companies, ISO 13485, Medical devices – Quality management systems – Requirements for regulatory purposes, and ISO 9001, Quality management systems –


Define Your Terms!

Requirements, define corrective and preventive action. Since complying with these standards is required to sell devices in Europe, Canada, and Australia, it makes good business sense for device firms to use these definitions. Drug and biologic companies, and clinical groups, are under no such requirement, but define your terms and provide training to all employees so everyone is using the same terminology.

The ISO definitions are:

• Corrective Action: Action to eliminate the cause of a detected nonconformity or other undesirable situation.

• Preventive Action: Action to eliminate the cause of a potential nonconformity or other undesirable potential situation.

5. Train employees. Provide frequent, ongoing training to all employees or staff. Don’t forget to train sales representatives on what a customer complaint is, and how they should rapidly report any that they receive.

Provide training on the following to individuals performing investigations:

o Your investigation and CAPA procedure(s)
o All applicable regulations and standards
o Root cause analysis
o Solution criteria*
o How to perform an investigation
o Your documentation and reporting requirements
o Report writing (since employees may be moving from simply filling out a form to creating a written investigation report)
o Interviewing (since investigators will need to be able to interview individuals at all levels)

*All solutions should prevent the recurrence of the problem, should not cause an unacceptable problem, should be within the control of your organization to enact, and should provide good value for their cost.

Teach everyone the key stages of an investigation:

1) identification and definition of the problem,
2) determination of whether to do an investigation (categorization/risk analysis),
3) planning the investigation,
4) root cause analysis,
5) identifying appropriate corrective and preventive action,
6) implementing the action, and 7) measuring the effectiveness of the action.

• Train everyone to carefully evaluate and select possible CAPA actions before they are implemented, and to confirm the effectiveness of the CAPA – and that it didn’t cause a greater problem – after implementation (the effectiveness checks).

• And teach everyone how to do a basic or preliminary investigation. Only ask experienced investigators or employees to perform more serious or difficult investigations (follow-up investigations).

By Barbara K. Immel

For further information take a look at Barb’s website:



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In News from GxP Perspectives:

CAPA Plans for Clinical Trials

Protocol Violations: Root Cause Analysis

Updates posted 28 JAN 2011- Read about the Academy of Medical Research Report by Nick Taylor in Outsourcing-Pharma

Public Comment Period is Open for New FDA Draft Guidance:
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Scam “clinical trial” targets the hard of hearing

December 30, 2009

It was enough to make my blood boil. A family member who has hearing problems passed me an announcement for a “Field Trial Notification” that contained wording that made it sound like a legitimate clinical trial. Things like, “You have been selected to receive this invitation to participate in this study” and “We will be selecting only 20 local residents as candidates for this field test at this time.” The notice gave three “inclusion criteria” similar to what you would see in a legitimate ad for a clinical trial. However, these folks are just peddling their product. There is no research going on and people who answer the ad are going to have to pay a price, which is never stated, for the hearing aid.

There are some dead giveaways that this isn’t a study of any kind. Three things are:

1. There is no clear statement of research, only the suggestion of a “study” and a “field test.”

2. It uses language such as “incredibly discreet” and “comfortable.”

3. It states that “Your satisfaction is 100% guaranteed.”

If this was a legitimate clinical trial an institutional review board (IRB) would have to approve the language in all advertisements and no legitimate IRB would ever allow such suggestive language. This is a scam to try to sell a particular brand of hearing aid, pure and simple. This type of deceptive advertising has been around since they invented snake oil. Its one of the reasons we have an FDA. The new leadership at FDA seems intent on going after the most fraudulent shysters, particularly with phony H1N1 “cures.” They’ve got a big job in front of them.

I’m all for alternative therapies and have an appointment with my acupuncturist tomorrow. I know some fine people using homeopathic medicines. There are also a lot of frauds out there and the ones who target seriously ill people with difficult health problems for nothing other than personal gain should be tarred & feathered and run out of town on a rail. (In my humble opinion.)

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