A former executive at Bennett Environmental Inc., a Canada-based company that treats and disposes of contaminated soil, was sentenced today to 50 months in prison for participating in money-laundering and fraud conspiracies in connection with contracts at a Superfund site in New Jersey, as well as impeding a proceeding before the U.S . Securities and Exchange Commission (SEC).

Joshua David Evans, 34, of North Bend, Wash., and Jeremy Lynn Andrew, 33, of Eugene, Ore., pleaded guilty today for their roles in NinjaVideo.net, a website that provided millions of users with the ability to illegally download infringing copies of copyright-protected movies and television programs in high-quality formats.

“Through this operation we are aggressively targeting those who are selling counterfeit goods for their own personal gain while costing our economy much-needed revenue and jobs,” said Attorney General Eric Holder.

Hana Amal Beshara, 30, of North Brunswick, N.J., was sentenced by U.S. District Judge Anthony J. Trenga in the Eastern District of Virginia.

Matthew David Howard Smith, 24, of Raleigh, N.C., was sentenced today in Alexandria, Va., to 14 months in prison for his role in founding NinjaVideo.net, a website that provided millions of users with the ability to illegally download high-quality copies of copyright-protected movies and television programs.

The seizures are the result of Operation Wreaking hAVoC, an FBI and Justice Department operation targeting the sale of stolen credit card numbers via the Internet.

Pharmacia Corporation and Bayer CropScience Inc. have agreed to pay $4.25 million to federal and state natural resource trustees to resolve claims for natural resource damages connected with the Industri-plex Superfund site located in Woburn, Mass.

The Department of Justice and the U.S. Environmental Protection Agency announced today an agreement with over three dozen companies and government agencies that will result in a $56.4 million cleanup of the “Malone Services Company” Superfund Site in Texas City, Texas, a former waste-disposal site near the shore of Galveston Bay.

"Attorney General Holder often says that fighting violence in our cities and building a fair and effective justice system – a system that keeps citizens safe and maintains its legitimacy in the eyes of everyone it serves – has never been more difficult, nor more urgent, than right now," said Acting Associate Attorney General West.

"As we work to help keep our children safe, we cannot view youth violence and violence against women as separate and distinct, but, instead, as intertwined. To realize our vision for safe and healthy communities, we must start with safe and healthy homes," said Acting Director Hanson.

Northern States Power Co. will begin cleanup of the Ashland/Northern States Power Lakefront Superfund Site in Northwestern Wisconsin under a settlement the Department of Justice and the Environmental Protection Agency (EPA) announced today.

"The message we’re sending is that youth violence is not inevitable. When communities engage partners across disciplines and use a data-driven, balanced approach – one that emphasizes prevention, intervention, enforcement, and reentry – they can reduce violence and improve outcomes for our youth," said Acting Assistant Attorney General Leary.

"By emphasizing collaborative partnerships, evidence-based and data-driven strategies and a balanced, holistic approach, we know we can help communities to curb violence and promote the health, safety and development of our young people," said Acting Associate Attorney General West.

The department said that this is the first time website domains involving cell phone app marketplaces have been seized.

The U.S. District Court for the Southern District of New York entered a consent decree between the United States and a company that operates fan club websites for popular recording artists such as Justin Bieber and Selena Gomez, the Justice Department announced today. The government’s complaint, filed in connection with the decree, charges the company with violating both the Federal Trade Commission (FTC) Act and the Children’s Online Privacy Protection Rule. The company has agreed to pay a $1 million penalty to settle these charges.

Another important step toward cleaning up the Quanta Resources Superfund site in Edgewater, N.J., was announced today by the Department of Justice and the U.S. Environmental Protection Agency.

Beatrix Boka, 34, of Hungary, pleaded guilty today before U.S. District Judge Aleta A. Trauger in the Middle District of Tennessee to one count of conspiracy to commit bank and wire fraud.

The United States has entered into two settlements worth more than $50 million to clean up contamination from the B.F. Goodrich Superfund Site in San Bernardino County, Calif.

Hungarian nationals Beatrix Boka and Aleksandar Kunkin were sentenced today to serve 36 months and 48 months in prison, respectively, for their roles in moving approximately $550,000 in illicit proceeds derived from an international online marketplace fraud scheme.

A former web producer for a Tribune Company-owned television station in Sacramento, Calif., was charged today in an indictment for allegedly conspiring with members of the hacker group “Anonymous” to hack into and alter a Tribune Company website.

A New Jersey jury convicted a former project manager for his central role in conspiracies that spanned seven years and involved kickbacks in excess of $1.5 million at two Environmental Protection Agency (EPA) Superfund sites in New Jersey, the Department of Justice announced today. The jury returned guilty verdicts on 10 counts charged in the indictment against Gordon D. McDonald, which was filed on Aug. 31, 2009.

Pamela B. Reid pleaded guilty last night to one count of filing a false individual income tax return for the 2006 tax year, the Justice Department and Internal Revenue Service (IRS) announced.

The Civil Rights Division and U.S. Attorney Carmen Ortiz announced today that they have moved to intervene in National Federation of the Blind et al v. HRB Digital LLC et al, a private lawsuit alleging disability discrimination by HRB Digital LLC and HRB Tax Group Inc., subsidiaries of H&R Block Inc.

W.R. Grace & Co, based in Columbia, Md., paid over $63 million to the U.S. government under its bankruptcy plan of reorganization to resolve claims for environmental cleanups at approximately 39 sites in 21 states.

Gordon D. McDonald, a former project manager for a prime contractor at two U.S. Environmental Protection Agency (EPA) Superfund sites in New Jersey, was sentenced today to serve 14 years in prison for participating in multiple bid-rigging, fraud and kickback schemes.

Acting Assistant Attorney General Jocelyn Samuels of the Civil Rights Division and U.S. Attorney Carmen M. Ortiz of the District of Massachusetts announced today that they have entered into a consent decree with HRB Digital LLC and HRB Tax Group Inc., subsidiaries of H&R Block Inc., to remedy alleged violations of the Americans with Disabilities Act.

Eric Omuro, of Mountain View, California, a.k.a “Red,” was arrested today following his indictment by a federal grand jury on charges involving the use of the mail and the Internet to facilitate prostitution, and multiple counts of money laundering

Earlier today, Associate Attorney General Tony West, Assistant Attorney General Stuart Delery for the Civil Division and members of the Department’s Elder Justice Initiative met with stakeholders in the field of elder abuse and financial exploitation to launch the Elder Justice website.

By Laurie Meehan

“I can’t get the IWRS to assign a kit number.”

“My ECG reports take forever to come back from the Core Lab.”

“The eCRF won’t let me create a new subject.”

“This stupid machine is blinking an error code again.”

Sound familiar?  Sprinkle in some colorful adjectives and it probably does -- these problems are common enough at clinical research sites.  Equipment and systems have become increasingly technical and specialized, and study site staff has had to contend with more technology than ever before.  And because of the proliferation of niche vendors who provide the new tech, sites have had to deal with more vendors than ever before, too.  



And how are problems like these typically resolved?  Someone at the study site works his/her way through a list of maybe 20 or more vendor contact numbers, places a call, navigates a series of menu options, and hopefully gets directed to someone who can help.  And that assumes the site calls the right company; with tightly integrated systems, it’s not always obvious in which vendor’s system the problem lies.  This is frustrating for sites.  It takes time.  It costs money (since “vendor wrangling” is seldom sufficiently covered in the budget).  And it keeps study staff from doing what study staff does best – run the study, work with the study volunteers, and keep them safe.

So what’s the solution? 

Hint: It’s Not Training
Calm down.  Of course, adequate training on equipment and systems is important. But training doesn’t solve every problem.  Training doesn’t keep equipment from malfunctioning.  Training doesn’t ensure vendors deliver what and when they’ve promised.  Training can’t anticipate every situation nor address an unusual site circumstance.  And training doesn’t turn people into infallible little machines; we make mistakes.  And so, in all these cases, we’re back to site personnel interacting with perhaps scores of vendors, by phone or email, all over the world.

The Solution: a Single Point of Contact
Q: How do you help sites interact with dozens of vendors?
A:  You don’t.  You do it for them.  Establish a single point of contact within the Sponsor* organization for a site to call when vendor issues arise. 

Why is this a good idea when the expertise to resolve the issue lies with the vendor?  Why is this a good idea when the introduction of a middleman may result in some inefficiencies?

Excellent questions.  Here are our responses. 

• Better Vendor Oversight.  When sites filter their vendor issues through the Sponsor, the Sponsor can more easily track vendor performance.  Are there vendors that provide low-quality solutions, are repeatedly late, or difficult to deal with?  At best, these vendors are wasting time and money, and aren’t good for business (let alone site relations).  At worst, these vendors are jeopardizing subject safety or study data integrity, and require immediate Sponsor intervention.

• Better Site Oversight.  When sites filter their vendor issues through the Sponsor, the Sponsor can more easily track site performance.  Are there sites that routinely use equipment and computer systems incorrectly?  (Yes, now’s the time for that training.)  Are there high-performing sites that are able to work independently?  This information has always been important, but in an RBM paradigm, it’s essential.  Adaptive monitoring plans rely on on-going site performance measurements so Sponsors can adjust resources accordingly.  A reduction in monitoring visits means less opportunity to assess a site’s comfort level with study technology.  The corollary of “if it ain’t broke, don’t fix it” is “if you don’t know it’s broke, you can’t fix it.”

• Ability to Identify Pervasive Problems. After the third or fourth site reports the same problem, it’s clear that this is not an isolated occurrence.  Knowing that, the Sponsor can work with the vendor to resolve the problem before other sites experience the same troubles.

• Better Functioning Sites.  We have a saying: “The Site Comes First."™  In our experience, all things being equal, Sponsors that put their sites first -- make things as easy as possible for the study coordinators -- get the best results.  They also build the good relationships that keep the best sites coming back to work on future studies.

• Better Functioning Vendors.  The efficiencies for the vendor here are clear.  Who wouldn’t rather interact with a single point of contact than field individual calls from multiple study sites?  Plus, with far fewer players, miscommunicating both problem descriptions and problem solutions is less likely to occur.  The Sponsor contact and the vendor contacts will eventually settle into common terminology and build a history regarding past issues and resolutions.

What Do You Think?
We know that not everyone espouses this idea, and we recognize there are probably other effective processes out there.  Sponsors, how do you help your sites deal with multiple vendors?  Sites, do you have experiences and/or suggestions you can share?  (Be kind, anonymize!)  Leave a comment here, visit our website, or send us an email.




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*When we use the term “Sponsors” in this post, we’re including CROs that take on Vendor Management responsibilities on behalf of Sponsors.

Anx·i·ety (noun)
The state of uneasiness caused by apprehension of possible misfortune.

Yep.  That’s the word that comes to mind whenever anyone mentions FDA inspections.

But anxiety often stems from a lack of control, and in a regulatory inspection, you have more control than you might think.  There are many steps you can take -- before, during, and even after an inspection is over -- that can give you a fair degree of control over the outcome.   Here, Polaris auditors Lauren Kelley and Michele Commins share some of those steps with you.



Pre-inspection Preparation
For-cause inspections may be unannounced, but routine FDA inspections of submission data are scheduled in advance*.  That means most inspections are not pop quizzes; they’re final exams.
Remember how happy you were when a teacher gave you access to a prior year’s exam to study from?  You knew the type of questions that would be asked.  You knew how to prepare.

So this is the first tip we’d like to share.  FDA has, indeed, given you a copy of their exam in advance, in the form of its Compliance Program Guidance Manual, CPGM 7348.811.  This is the document all FDA field investigators use to conduct inspections at clinical sites.  It outlines in great detail what documents investigators will review, what dates they’re going to verify, what processes they’ll evaluate, what data they’ll collect, and what records they’re going to compare.  Despite its rather uninspired title, this is your copy of the final exam.

You know cramming is a risky strategy, so the earlier you get familiar with the CPGM the better.  Inspection readiness is a state of preparedness more than it is a laundry list of activities; it takes some time to get there.

When the Inspector’s in the House
According to the CPGM, one of the first pieces of information the FDA investigator will obtain is a list of all of the studies performed by the clinical investigator, including protocol number, sponsor, and study dates.  So even though FDA has scheduled its inspection with you, and has told you what study the investigator is coming to inspect, any study is fair game.  An FDA investigator can look at any document she wants, or talk to any staff member he chooses, whether related to the “assigned” study or not.

Most of your preparation will have been study-specific; questions about other studies will catch your staff off-guard, and a review of records for other studies may find them less than inspection-ready.  So here’s our second tip.   Avoid anything that might pique the investigator’s curiosity about a study that is not the original subject of the inspection.  Make sure the room you reserve as your investigator’s “home base” is free of any documents, reports, notes, phone lists, and post-its.  Make sure you tidy up offices, workspaces, and facilities site-wide, and keep extraneous chatter in check.

After the Visit
If your FDA inspection resulted in zero observations, then stop reading, thank your awesome staff members, and go celebrate.  If, however, you did receive a Form FDA 483, it’s probably not the end of the world, but you do have some work to do.  Our third tip is this:  remember that the sponsor/CRO is your ally here.  They have as much invested in FDA’s assessment of your study data as you do, and they have the regulatory, QA, even legal resources that you might not.   You’re not required to formally respond to 483s, but if you do, you’re likely to receive a more favorable Establishment Inspection Report (EIR) in the end.  Let your sponsor/CRO help you with your response.

Tips Do Not a Plan Make
Tips are helpful, but you’ll need more than that to ensure a successful FDA site inspection.  You need an inspection readiness plan -- a plan that you document and keep current.  All site staff members need to train on the inspection procedures and the individual roles they will play.  (Fourth tip: don’t forget to train your temporary employees; an office temp working at the receptionist desk could be the first person your FDA investigator speaks with.)

A Last Thought
Inspections are stress-inducing events, and nervous people make mistakes.  Investigators know this, and expertly exercise the “pregnant pause,” knowing how difficult it is for people to withstand an excruciating silence without volunteering unsolicited information.

So one last tip:  conduct a mock inspection before the FDA comes to visit.  It will stress test your procedures and identify improvements you need to implement.  A thorough mock inspection will give staff members an opportunity to rehearse their roles and interview techniques so they can execute your plan and speak to the FDA investigator with confidence.

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* For-cause inspections are also known as Investigator-oriented, and routine inspections are also known as study-oriented.

 A version of this article originally appeared in InSite, the Journal of the Society for Clinical Research Sites

As a sponsor or CRO, you understand the importance of a thorough site selection process. A site needs to be able to meet enrollment targets and time frames, protect the rights and safety of study participants, execute the protocol, deliver quality data, and maintain GCP compliance. That’s what your site feasibility surveys and pre-study visits are designed to evaluate. And as you’re assessing a site’s abilities, the site is conducting its own feasibility process. They’re mining their patient database and assessing inclusion/exclusion criteria. They’re reviewing staff credentials and ensuring they have adequate resources to manage the number of subject visits and collect the data the protocol requires.

But when we conduct GCP audits, we find there’s one perspective that is sometimes overlooked by both sides: the needs of the study drug itself.




Study Drug Attributes Affecting Site Selection Process

IP Environment.  Aside from needing sufficient storage space, many drugs have special storage requirements. Does the site have the equipment and resources needed to maintain and adequately monitor and record environmental conditions such as temperature or humidity? Do they have agreements with their vendors that guarantee a specific response time for repairing or replacing faulty equipment? If they lose electricity, do they have back up power, or at least provisions to move the IP off-site? (This is a common auditor question in hurricane-prone areas.)


Preparation of Study Drug.  Does your investigational product need to be reconstituted in a liquid? Do doses need to be compounded in different concentrations? Does the protocol require that an IV solution be prepared, filtered, and sterilized? These activities take time, specially trained personnel, and sometimes specialized equipment such as ventilation hoods. If your protocol demands an involved IP prep, your feasibility survey must include questions that allow you to assess these site capabilities and your pre-study visit should definitely include some time in the pharmacy. 

Drug Administration. Handing over a bottle of capsules to a study participant is one thing; inserting a butterfly catheter into an antecubital vein is something else again. If drug administration is very invasive, you’ll want to verify that the site has taken this into account when providing you enrollment projections. During subject visits, staff members may have to calculate doses, give intramuscular injections, perform infusions, or conduct sterilization procedures. You’ll want to verify that site staff has this expertise if required. Some clinical trials require a blinded dispenser who cannot be involved in any other study procedure or activities. If so, does the site have the resources for this?

Site Selection: it’s not just the PI, it’s the IP too
The study success and patient safety are jeopardized when a site can’t meet its enrollment target or doesn’t have the resources to execute the protocol. IP requirements can affect a site’s ability to do both. It’s critical that your site selection process – both your feasibility questionnaire and your pre-study visit – evaluate how well the site can meet the storage, preparation, and administration requirements of the study drug.

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A version of this article originally appeared in InSite, the Journal of the Society for Clinical Research Sites.

Photo Credit: By Harmid (Own work) [Public domain], via Wikimedia Commons

When I was a teenager, my grandfather would invite my new boyfriends to run short, pointless errands with him, just so he could watch them drive. He said he could tell a lot about a boy’s character simply by observing his actions behind the wheel. Did he stay under the speed limit? Did he use his signal when he was switching lanes? Did he slow down when children were playing near the road? If so, it was a good sign that the boy was generally a careful and attentive fellow. If not, it was an early indication of reckless tendencies, and I would do well to be on my guard.

What does this have to do with PI oversight?



As Sponsors and CROs, you’re sometimes forced to make site selection decisions based on a limited set of criteria that you deem to be – hope to be – reflective of the site as a whole. In a short space of time, you need to assess a PI’s commitment to study oversight. On what should your pre-study “test drive” focus to help you gauge the level of care and attention a prospective PI will devote to your study?

We have some suggestions.


Assessing Attention to Detail
Any GCP-compliant site can produce a set of current CVs, job descriptions, and training records; they’re essential documents. But the most attentive sites are able to show you more than a collection of records during your pre-study visit with them. These sites keep a complete, organized set of uniform records and can describe their tight system for maintaining it. All documents for each staff member are found in dedicated tabs inside a records binder, or are equally well-organized in an electronic records system. All CVs are in a standard format so Sponsors can easily compare qualifications across individuals. Every document is current; CVs are up to date, and there’s a system in place to track which medical licenses are expiring when. Training records are comprehensive and include training on GCP regulations, site SOPs, and EMRs.

This is not sexy stuff. That’s why it’s a good indicator of PI oversight.  A site that is disciplined enough to keep such tight control over its personnel records is likely to carry that control into all aspects of trial execution.

Assessing Commitment to Protocol Compliance
During site initiation visits, Sponsor/CRO staff is on site to conduct protocol training; all study sites start off the same in this respect. But protocol amendments are inevitable, and sometimes – though nobody’s happy about it – frequent. You need assurances that a site’s response to each amendment will be swift, well-coordinated, and deliberate. Ask the prospective PI, “What procedures does your site follow for managing protocol amendments?”

The A answer:
“When a protocol amendment arrives, we convene a special team meeting to review the changes and discuss their effects. For example, if additional safety tests are required, the team discusses who shall be delegated to perform them? Do we have adequate time scheduled into the visit for any additional procedures the amendment requires? How will I be demonstrating oversight of any new test results? Once we’ve asked and answered these kinds of questions, we document attendance at the meeting, record assignments of delegated duties, and publish meeting minutes.”

The F answer:
“I email the amendment out to my team. I assume they’re all adults and know how to read.” (#TrueStory)

Just Ask
After reviewing essential documents and protocol amendment procedures, you should ask about other PI oversight mechanisms the site has in place. A good prospective site might tell you the PI holds biweekly meetings to review the items raised during monitoring visits. A PI may block out time at regular intervals to review adverse events and other study documents, and sign off on labs. A PI who values staff excellence may actively encourage and support Study Coordinator certification; some may even require it after an initial period of employment. In the past, we’ve worked with sites that have established internal Quality Control procedures, some maintain CAPA programs, and others conduct mock inspections.

There’s a wide variety of responses that can give you confidence a prospective PI is committed to running your study in a constant state of control. Whatever oversight measures are discussed, remember to ask how they will be documented, so during the study you’ll be able to verify that each activity is being consistently carried out.

Epilogue
After running an errand with a boy I met at college, my grandfather happily reported back to me, “He didn’t roll through a single stop sign coming down Green Hill Road. He’s all right, that one.”

My grandfather, a retired police detective for the city of Pittsburgh, knew how to read a person. That boy and I celebrated our 30th anniversary last month.

I was a child bride.

If you found this article helpful, you might also like:
Anticipating Tensions Between Clinical Care and Study Protocol
Avoiding Protocol Deviations

Sites frequently want to know how they can stand out to Sponsors and CROs to win more studies.
Our advice: Implement internal QC procedures.

Sponsors and CROs we work with consider a tight quality control program to be evidence that a site can be counted on to produce reliable data. It shows that managing quality at your site is a continual process, and doesn’t wait for monitors to arrive. In a risk-based monitoring environment, this is an increasingly compelling attribute.

Where to Start: The Usual Suspects
It makes sense for you to focus your QC efforts on those areas where you’ve historically had the most problems. If the phrase “trend analysis” makes you want to jump through a window -- it's okay -- you can climb back inside. You don't have to do a trend analysis. We've identified 3 areas in which audit findings are common and how you can avoid them.



Adverse Events (AEs) and Concomitant Medications (ConMeds). Often two sides of the same coin, AE and ConMed documentation needs to tell a consistent story. If source documents indicate a study participant had a sinus infection, it must be documented on an AE page, and any associated medications documented on the ConMeds page. A medication noted on the AE page must have a corresponding notation on the ConMed page. And all start and end dates must match across the source, AE, and ConMeds pages.

Drug Accountability Records. Calculating compliance percentages and counting pills are positively uninteresting tasks, easy to mess up, and involve math (which for some people triggers terrifying flashbacks of word problems about trains leaving stations). Is it any wonder that drug accountability records are frequent sources of error? Do some spot-checking: verify that the number of returned tablets matches the tallies recorded for them and recheck compliance calculations.

Essential Documents. Maintaining a complete, organized, uniform set of essential documents is an important, yet decidedly unsexy task. That’s why it’s a good indicator of your commitment to quality; a site that is disciplined enough to keep tight control over its essential documents is likely to carry that control into all aspects of trial execution. Make sure to file all documents associated with protocol amendments, such as IRB approvals and revised informed consent forms -- our auditors find these are the items most frequently missing from the essential document set. 

Write It All Down
Document your QC procedures in an SOP. It will serve as training material for site staff and a repository for worksheets and checklists.

There’s no magic organization for this QC SOP. A general set of instructions could outline how reviewers can verify that all documents follow ALCOA principles. For example, on (paper) source documents, are all pages and required signatures present? Are entries legible? Are corrections initialed, dated, and explained? Does the data make sense and lie within expected ranges? Have all data elements been populated? (Tip: turn the paper upside down to catch missing data.)

Checklists that are focused on particular types of documents should be as specific as possible. For example, QC reviews of source documents for screening visits would verify that the correct informed consent form was used, administration of consent was documented, medical release forms were sent if required, demographics were correct, all labs were received, reviewed and signed, all protocol assessments were completed, and all inclusion/exclusion criteria were met and documented.

A Virtuous Cycle
While designed to control quality, performing QC over time may actually improve quality. Results of QC reviews often suggest revisions you should make to your tools and operations to reduce error in the future.

Okay, you can climb back through the window again -- no one said CAPA. (But wouldn't that be impressive?)


Showcasing Site QC Processes
Does implementing a QC program require resources and time? Yes, and that’s the point. It’s evidence to Sponsors and CROs of your commitment to running a quality study. Not only that, but it demonstrates a proper respect for your study participants by ensuring their data can be used.

Oh, and make sure you highlight your QC program on feasibility questionnaires. It’s something to brag about.

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A version of this article originally appeared in InSite, the Journal of the Society for Clinical Research Sites

In an effort to tease out the priorities of a clinical study site audit, I asked six of our most experienced GCP auditors the following question:

If you only had one hour to conduct a study site audit,
what would you look at?
[Obligatory warnings:  Do not try this at home. This is just a simulation. Caveat lectorem. Dinosaurs in the mirror are bigger than they appear. Et cetera.]

Of course it’s not possible to conduct any kind of meaningful audit in so short a time, but it’s an interesting thought exercise because it gets to the heart of study site risk.
In order to respond to this question, the auditors needed to ask themselves:

(1) What are the greatest site risks to a study?
(2) Where can evidence be found that those risks are being managed?

Answering the first question is pretty easy. The very first paragraph of ICH E6(R2) tells us “Compliance with this standard provides public assurance that the rights, safety and well-being of trial subjects are protected…and that the clinical trial data are credible.” So there it is: the reason GCP exists. When we conduct clinical research, our highest priorities are human subject protection and data integrity. It follows, then, that jeopardizing these obligations is our greatest risk.

So with only an hour to evaluate whether a study site is managing these risks, we can move on to the second question. What would our audit (now referred to as “hour audit”) look like?

IRB Approvals

Hour Auditor has decided to spend the first twenty minutes at the site reviewing IRB approvals. Are all of the IRB approval letters in the Investigator Site Files (ISF)? Is the protocol that’s being executed the same version that the IRB approved? Have the protocol amendments and all of the associated Informed Consent Forms (ICFs) also been approved?

Missing approval letters aren’t necessarily the end of the world. It’s quite possible that the required approvals are sitting on the sponsor portal, having been received from a central IRB. Their absence from the ISF could just be a clerical error. However, it’s a first-order finding if the site was responsible for getting approval from its local IRB and failed to do so. The IRB would have to be notified. The FDA would have to be notified. Without review and approval from an ethics body, the safety of study participants is jeopardized and their rights violated. Everything stops.


Informed Consent

With forty minutes left to go, Hour Auditor spends the next twenty minutes reviewing participants’ ICFs. The selection of these participants may be random or targeted, depending on the results of the IRB approval review. Has each participant signed every applicable version of the ICF? Were they signed before any associated study procedures were conducted? If not, was the delay noted in the subject notes? How was the situation remedied? Was there a CAPA to ensure that any other incidents were corrected and future occurrences prevented? Was the IRB informed?


Inclusion/Exclusion Criteria

Now down to the final twenty minutes, Hour Auditor asks to see the Inclusion/Exclusion (I/E) criteria for two screened and enrolled participants. Most likely, the particulars of the study -- the vulnerability of the patient population, the therapeutic area, and the protocol complexity, among other things -- would drive the selection.

We’re running out of time, and this could be our final stop. With so much else to look at, including source data, IP accountability, staff qualification and training, and Adverse Events reporting, why focus on I/E criteria? Because they give us a glimpse of many aspects of study conduct all at once. When a site can assess complex I/E criteria correctly, it demonstrates protocol compliance and a commitment to producing reliable study data. Examining I/E criteria also gives Hour Auditor a chance to assess source data quality and provides further assurance of subject safety.

Best Laid Plans
As with any audit, particular findings at any step could (and should) alter the plans for this one-hour visit. If the ICF review left Hour Auditor concerned about fundamental flaws in the IC process, the rest of the audit might be spent trying to determine the extent of the problem. An incidental discussion could raise red flags about staff proficiency that may have Hour Auditor poring through protocol training records or scrutinizing the Delegation of Authority log. (Plus, Hour Auditor really, really wants to take a peek at the IP accountability records, and so may find a reason to do so*.)

The point of this thought exercise was to consider (1) the obligations of the clinical research industry to protect subjects and produce reliable data, (2) where the biggest risks to that obligation lie, and (3) how site audits should be prioritized to ensure those obligations are being met and those risks are being managed.

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*The auditors involved in this discussion did their best to honor the absurdly artificial time constraint I gave them. That meant foregoing activities no self-respecting auditor could bear to forego. This paragraph recognizes some of those activities. (Thank you all. I know this hurt.)

A version of this article originally appeared in InSite, the Journal of the Society for Clinical Research Sites.

Alarm Clock Image via Good Free Photos

Q: Do study site personnel need to be able to answer questions about sponsor-provided computer systems during an inspection?

A: Yes, and there’s a simple thing that sponsors and CROs can do to prepare their sites.

This excerpt was lifted from an online, interactive course entitled “Developing a Part 11 Compliance Plan in Clinical Research.” While the course mainly targeted sponsors and CROs, who have the heaviest regulatory burden in this area, sites also have Part 11 and validation concerns, as demonstrated by this question.

Presenter Lisa Olson, a CSV/Part 11 expert with Polaris Compliance Consultants, briefly described her recommendation, which is both simple and effective. (And since that is total catnip to a compliance blogger, I interviewed her after her presentation to develop the following piece.)

So here it is. Here’s what she said...

Clinical research sites rely heavily on technology to store and manage study data, so regulators are focusing on computer systems and electronic data more than ever before. Many of the systems – such as Electronic Data Collection (EDCs), Interactive Response Technology (IRTs), and e-diaries – are selected and largely controlled by sponsors, CROs, and/or third-party vendors. That doesn’t mean, however, that site staff won’t be expected to answer questions about these systems during a regulatory inspection. Quite the contrary: site personnel are responsible for the integrity of the data these systems house. They need to be able to demonstrate the knowledge required to meet their regulatory obligations.

No one is expecting site staff to be computer specialists; the expertise on these systems resides within the sponsor/CRO/vendor organizations. But the better a site can satisfy a basic, frontline inquiry into the systems it uses, the less likely it is that an inspector will pursue additional lines of questions.

So how can sponsors and CROs help?

They can provide a set of short summaries (one page per system) that answer the questions regulators are likely to ask site staff members. Filed in the Investigator Site File (ISF), ready for use, these summaries will be valuable resources.


The Basics

First, sponsors/CROs should supply identifying information: the name of the system, the vendor, the version of the system currently being used, and a few sentences that describe what the system does.
User Access and Control

To ensure both data integrity and compliance with Part 11 e-record/e-signature regulation, it’s essential that access to a system be controlled and data entry/updates be traceable to a specific person. To that end, the one-pager should describe how unique logins are assigned and how users are restricted to activities appropriate to their roles in the study. A monitor requires read-only access to an EDC system. A study coordinator needs to be able to enter and change EDC data. A Principal Investigator must be able to sign electronic Case Report Forms (CRFs). The role determines the access. Staff should also be able to briefly describe how an audit trail captures metadata that show what data were entered/altered, by whom, and when. (And someone, though not everyone, needs to be able to demonstrate how the audit trail can be used to piece together the “story of the data.” That, however, is too much to ask from our one-pager.)

Validation 101

It would be unusual for site personnel to have detailed knowledge of Computer System Validation (CSV) activities. Nevertheless, the one-pager could include a single line that confirms that the system was validated and by whom. A contact number could be included in case a regulator asks for more information or wants to see validation documents.

Where’s The Data?

Regulators will often ask where system data are stored. The answer to that question can be a simple sentence: The data are hosted by the EDC vendor at such-and-such location, or stored at the CRO, or sit on a local server within the site’s IT department.

Finally, the last line of our one-pager could be a simple statement prepared by the sponsor, CRO, or vendor, confirming that the data are protected wherever they are being stored. The data center is secure and environmentally controlled; the data are backed up to protect against loss; the system is accessed via the web through an encrypted channel -- whatever protections apply.

Conclusion

Regulators are increasingly focused on the integrity of study-related data, and that means added scrutiny of electronic systems and records. More inspections are being conducted mid-study so regulators can evaluate and ask about live systems in current operation. It’s very difficult for sites to field these questions without help from the organizations who make the decisions and have the expertise.

It’s okay to tell an inspector, “I don’t know.” (And it’s always preferable to admit that than to improvise an answer.) But say it too many times, and it casts doubt on a site’s ability to produce and maintain reliable study data. That’s in no one’s interest.

It shouldn’t be overly burdensome to develop a one-page summary sheet for each system so site personnel can address an inspector’s questions on the spot. The Investigator Meetings or Site Initiation Visits would be a good opportunity for sites to raise this point with their sponsors/CROs.

Lisa Olson will be giving an encore presentation of “Developing a Part 11 Compliance Plan in Clinical Research,” on March 24th. She describes all the elements that regulators and clients will be expecting, and since sponsors and CROs can’t implement everything all at once, Lisa prioritizes the activities necessary for developing your plan. You can register for the online course, sponsored by the Life Science Training Institute, here. Use the promotion code olson to receive a 10% discount.

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