Clinical Labs & GCP


FDA lab GCP

GCP for Clinical Laboratories

How to assess clinical laboratories for GCP compliance is one of the more difficult issues facing GxP professionals. Is CLIA the gold standard? How do the good laboratory practice (GLP) regulations impact clinical labs? Isn’t there a handy checklist out there somewhere? What do people mean by “GCLP?” I have been dealing with this issue a lot of late and people are really all over the map. Here are some of the approaches I take, along with a handy-dandy reference list at the bottom of the post.

First, let’s look at the easy part. The primary regulation dealing with clinical laboratories is the Clinical Laboratory Improvement Amendments (CLIA). Wow, that’s simple. However, CLIA specifically states that it does not have jurisdiction over research. CLIA covers the day-to-day laboratory tests that your doctor orders to check up on your cholesterol or hematocrit. For these routine tests, FDA recognizes CLIA certification as an acceptable standard. FDA also recognizes other certifications such as from the College of American Pathologists (CAP). However, FDA does not have its own laboratory program. No, the GLP regulations (Part 58) just don’t apply here. My advice is to keep them on the shelf.

GCP Lab FDA

Research Continues into New Laboratory Methods

However, things can get more complex. Not all laboratory tests are CLIA certified, there is a whole lot of research going on out there. Research methods are being developed every day. To make matters worse, just because a lab is CLIA or CAP certified, it does not mean that they have clinical trial experience and knowledge of kit building or blinding procedures. You need to go to their laboratory and see if they are equipped to perform the tasks in your statement of work. You need to perform a chain-of-custody tour to determine that your samples will be handled and analyzed in an appropriate manner, if there is “quality control at each stage of data handling” (ICH E6 Section 5.1.3).

One document that will come in handy is the FDA Guidance for Industry: Bioanalytical Method Validation. If you have a new laboratory method, it should be validated. What about an audit plan? I use the European Medicines Agency (EMA) GCP Inspection Guidance on Clinical Laboratories (Annex II). Links to both of these documents are listed below. The important thing to remember is that you have critical safety and efficacy endpoints being evaluated by the lab and they are highly importance to your study. Give the laboratory the attention it deserves.

GCP lab clinical trials FDA

Tour the Laboratory

Chronological order is a useful tool in assessing a laboratory. Follow the route of the samples starting with kit building, shipment to the sites, receipt from the sites and how they make it through the laboratory. Remember, the majority of laboratory errors take place Before sample analysis, in the pre-examination phase (source: CDC). In addition, there are more errors reported in the post-examination phase than the examination phase itself. Reporting is of critical importance. Your NDA or PMA might depend on the accuracy of those reports.

I have seen many checklists for conducting clinical laboratory audits. Most of them have issues that can impact their effectiveness. Your audit should be protocol-specific. The lab needs to be able to conduct the analyses required by the protocol. That’s why I use the EMA GCP Inspection Guidance for Clinical Laboratories as a basic audit plan. EMA has a GCP inspection program for clinical labs. Another important point is that not only do you need to pre-qualify a lab, you need to go back during the trial and audit live data. This is true for any critical vendor.

GCP Lab

There are a number of resource documents available

Many organizations are working on the clinical laboratory dilemma. You will hear the term “GCLP” quite a bit (for good clinical laboratory practice). It is important to remember that there is not one consistent standard on what GCLP is. Wouldn’t it be nice if we did have a consistent GCLP standard recognized by the world’s regulatory authorities? Here are some important references for clinical labs and GCP. Feel free to make additions to this list in the Comments section below.

EMA GCP Inspection Guidance for Clinical Laboratories

FDA Guidance for Industry: Bioanalytical Method Validation

College of American Pathologists Website

Clinical Laboratory Improvement Amendments (CDC)
(This site has links for genetic testing and Waived Testing)

GCLP – UNICEF, UNDP, World Bank, & WHO

MHRA: Good Clinical Practice for Clinical Laboratories – (Please see the comments/discussion on this.)

On The Blogroll: Dark Daily: News for Clinical Laboratories & Pathology Groups

====

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 LinkedIn group (below).

====

Draft Guidance: Considering Whether an FDA-Regulated Product Involves the Application of Nanotechnology. This guidance is open for public comment for 60 days (approximately August 7).
====
FDA has announced a new draft guidance document. Public comment is due by 25 July 2011:

Guidance for Clinical Investigators, Industry, and FDA Staff: Financial Disclosure by Clinical Investigators

===

FDA

On LinkedIn

Please join GxP Perspectives on LinkedIn at:

GxP Perspectives LinkedIn Group

====
Please Leave Your Comments & Expertise on GCPs & Clinical Laboratories
====

8 Responses to Clinical Labs & GCP

  1. Jim Sheets says:

    Hi Carl,

    My preferred reference for this type of audit would be MHRA’s “Guidance on the maintenance of regulatory compliance in laboratories that perform the analysis or evaluation of clinical trial samples”

    I find that the FDA guidance on bioanalytical method validation is not suitable for this lab type, but more suited to GC/MS/HPLC work or immunoassays.

    One pet peeve of mine is when Sponsors try and turn a hospital clinical laboratory into a bioanalytical laboratory…hoping that a specialty biomarker assay can be easily developed and validated there. CLIA standards will not necessarily meet all of your GCP data integrity expectations (e.g., data management, software validation, sample stability measures, %CV intrarun precision and accuracy, criteria for repeat analysis/reporting). Data integrity and test result qualification considerations can be quite different. A CLIA or ISO certificate in one’s hand does not get you completely off the hook. It depends on what you’re analyte.

    Jim

  2. Robyn says:

    Another great blog! I always learn something new when I read your blogs. Keep up the good work.

  3. David Montgomery says:

    The EMA documents are helpfu and I agree with Jim about the MHRA document.

    Interestingly, the MHRA lists this as Good Cilinical Practice for Clinical Laboratories on their website

    http://www.mhra.gov.uk/Howweregulate/Medicines/Inspectionandstandards/GoodClinicalPracticeforClinicalLaboratories/index.htm

    I particularly like section 4.2

    “It therefore follows, that all staff involved in the analysis or evaluation of clinical trial samples should receive GCP training commensurate with their roles and responsibilities.

    It is appropriate for laboratory staff to receive periodic GCP refresher training. Such training is especially important following changes to statutory regulations and associated guidance documents.”

    I suspect this gives clues to their thinking on GCP on a broader basis.

    David

    • GxP Perspectives says:

      Thanks to David and Jim for information on the MHRA document. I will put the link into the post’s reference documents.

  4. Deb says:

    Great Blog! However, it brings additional questions to mind.
    What are your thoughts on lab normal ranges?
    Does it matter if normal ranges are ‘purchased,’ pulled out of a reference material, or actually established by the lab? In my limited experience, some lab facilities create a separate, dated list of lab normals with values accumulated over time. Other facilities include lab normals in the actual assay report for a particular subject and refuse to provide a unique list or source for the info.
    Your comments would be appreciated.

  5. DERAM Philippe says:

    Thank you for this excellent blog!

    Please note that the MHRA guidance (http://www.mhra.gov.uk/home/idcplg?IdcService=GET_FILE&dDocName=CON051910&RevisionSelectionMethod=Latest) was incorporated in 2010 by the European Medicines Agency in a Reflection Paper submitted to public consultation (see http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2010/09/WC500096987.pdf)

    FYI, a reflection paper “may be developed to communicate the current status of discussions or to invite
    comment on a selected area of medicinal product development or a specific topic. It can provide a
    framework for discussion or clarification particularly in areas where scientific knowledge is fast
    evolving or experience is limited. A reflection paper does not provide scientific, technical or
    regulatory guidance, but may contribute to future development of such guidelines, or related
    documents.”

    Philippe Deram

    • GxP Perspectives says:

      Thank you, Philippe- As someone from the U.S. I stumble across Reflection Papers infrequently. There is an excellent one on the TMF Page at the top of the Blog on electronic source documents. It is referenced in the post “Reflecting on the TMF” from about a year ago. I equate, in general terms, a Reflection Paper as similar to an FDA Draft Guidance document. They have some very good information. I adopted the clinical trial records attributes “Complete, Consistent, Enduring, and Available when needed” from a Reflection Paper.
      Carl

  6. Tina Avanzato Chiodo says:

    Thanks, Carl, for an excellent discussion and useful links.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s

%d bloggers like this: