FDA Guidance Documents on GCP: Periodic Review

June 26, 2011

FDA Comment Period Proposed Guidance

FDA Comment Period for Proposed Guidance on Financial Disclosure

The FDA has released a number of guidance documents in the past few years that gives the Agency’s current thinking on Good Clinical Practice and other regulatory issues. Some of these documents change the “conventional wisdom” on conducting clinical trials. One document: “FAQs on the Form FDA 1572, Statement of the Investigator,” changes the way we look at putting research coordinators on the FDA 1572. Another document, “Adverse Event Reporting to IRBs,” changes the old rule of thumb to Always report a serious adverse event (SAE) to the IRB within 15 days (or less). Currently, FDA is soliciting public comment on the Draft Guidance Document, “Financial Disclosure by Clinical Investigators.” The comment period is the opportunity for the public, researchers, and regulated industry to comment on FDA’s guidance on financial disclosure and compliance with 21 CFR Part 54.

FDA guidance document periodic review

Periodic Review of SOPs


Why am I bringing up the issue of guidance documents?
Every organization that writes standard operating procedures (SOPs) to maintain compliance with FDA regulations should have a policy in place to perform Periodic Review of those procedures. Any periodic review should include a review of guidance documents from FDA and other regulatory agencies. There have been more than one Form FDA 483, Inspectional Observations, that have listed the failure to perform Periodic Review of SOPs. Look at the “Reference” section of your SOPs. Is it current? Are you keeping up with what FDA and EMA are saying?

Here are several documents that have been released of late that I think should be on any periodic review of SOPs:

Draft: Financial Disclosure by Clinical Investigators

FAQs on the FDA 1572

Supervisory Responsibilities of Investigators

Adverse Event Reporting to IRBs

MHRA: Clinical Laboratories

EMA: Pharmacovigilance and Risk Management

Finally, I think it is important to return to a final rule and look at the “preamble.” This is the discussion of a proposed rule (regulation) and the public comments on it during the rulemaking process. Here is the lengthy preamble to the 1987 rewrite of the IND regulations, 21 CFR Part 312. In part 3 of the preamble, you have to scroll all the way down to access part 2 and then scroll all the way down to get to part 3, you can see what FDA said about transferring responsibilities to a CRO. Very interesting reading:

Part 312 Preamble

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(Graphic on upper left is “Freedom of Speech,” by Norman Rockwell.)
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8 July UPDATE: There is an interesting FDA Press Release regarding new anti-smuggling measures and a new Draft Guidance Document on dietary supplement ingredients.

On The Blogroll: FDA Matters discusses the new FDA import initiative

The Medicine Show on Forbes discusses the decline in drug approvals.
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FDA Releases Draft Guidance on “Artificial Pancreas” to Fight Diabetes

June 21, 2011

FDA diabetes artificial pancreas

FDA Guidance for "Artificial Pancreas"

FDA released a draft guidace document for development of an “artificial pancreas,” a highly anticipated step in the fight against diabetes. At one time the onset of type 1 diabetes, where the body stops producing insulin, was always fatal. Then, in 1922, scientists from the University of Toronto gave the first injection of insulin to a 14 year old boy with type 1 diabetes. The experiment was a success and one of the major achievements in the history of medicine. However, this would be the first of many steps in fighting diabetes mellitus. Two of the scientists, Dr. Frederick Banting and Professor John Macleod won the 1923 Nobel Prize for Medicine which they shared with two other members of their team, Charles Best and Bertram Collip. And a new Nobel Prize winner may be working on an artificial pancreas right now.

The concept of an artificial pancreas or a “closed loop” system is that a diabetic could automatically have their blood sugar analyzed and in real time inject insulin to maintain a normal glycemic level.

artificial pancreas FDA

Researchers are Focusing on the "Artificial Pancreas"

Although there have been many advances with insulin pumps and continuous glucose monitors, the devil is in the details on how to regulate the amount of insulin supplied to the diabetic. It is hardly an easy matter.

Most diabetes researchers are looking into the concept of an artificial pancreas as opposed to replacing the islet cells in the diabetic’s pancreas that create insulin. It is the destruction of a diabetic’s islet cells that causes type 1, insulin dependent, diabetes. The Toronto researchers originally called their discovery “isletin.” Type 2 diabetes, once referred to as “adult onset” diabetes, is currently in epidemic proportions in the United States. It impacts the body differently than type 1 diabetes.

The development of an artificial pancreas requires the use of sophisticated medical devices, many of which are already approved. However, it requires the devices to communicate with each other and the development of an algorithm to measure the right amount of insulin to be administered at the right time. No easy task.

FDA guidance artificial pancreas

Draft Guidance Discusses Clinical Trials & Applications for Approval

It is also a difficult issue to regulate. FDA is responsible for ensuring that any artificial pancreas system is safe for the user. The new draft guidance lays out a step-by-step approach for researchers through the regulatory process, for “The Content of Investigational Device Exemption (IDE) and Premarket Approval (PMA) Applications.” The FDA press release states:

“Our goal is to provide a clear pathway for artificial pancreas development so that people with diabetes can benefit from innovative medical devices,” said Jeffrey Shuren, M.D., J.D., director of the FDA’s Center for Devices and Radiological Health. “Getting a safe and effective artificial pancreas system to Americans with type 1 diabetes is an FDA priority.”

The draft guidance is for an “early version of an artificial pancreas system.” There is a 90 day comment period from the date the guidance is issued (22 June 2011). A seperate guidance on more autonomous artificial pancreas systems is expected to be released by FDA by the end of 2011.

FDA Press Release

Draft Guidance…Low Glucose Suspend (LGS) Device Systems

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On the Blogroll: Top 40 FDA-Related Websites (and tweeters)

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Clinical Labs & GCP

June 12, 2011

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

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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).
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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

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