Malaysia, incoming host of APEC, will rally the forum to ensure that the ‘”benefits from trade, investment, and economic cooperation are felt and enjoyed by our people,” said Prime Minister Dr Mahathir Mohamad as he launched APEC Malaysia 2020.

Chinese Taipei has voluntarily contributed USD 550,000 in funding to support APEC initiatives that advance regional economic integration and inclusive sustainable growth across the Asia-Pacific.

APEC’s 21 member economies will finalize in 2020 a new vision for the forum’s next phase, said the APEC Secretariat’s Executive Director Dr Rebecca Sta Maria.

An APEC Business Travel Card mobile application will make travel easier and more secure

2020 APEC Science Prize Open for Nominations

Business leaders from around the Asia-Pacific met in Sydney last week to discuss the year ahead

The challenge: Innovative mobile apps and platforms that empower the aging society

Reflecting the discussions of the Health Working Group which met at the First APEC Senior Officials Meeting, 7-8 February 2020, Putrajaya, Malaysia

Business leaders from the Asia-Pacific region called for APEC leadership and cooperation to combat the grave challenges to health and economies posed by the COVID-19 pandemic.

Regional cooperation key to containment and rebound

Medical supplies and personal protective products are facing barriers worldwide

Trade Ministers agree to work together towards a healthy, resilient and inclusive Asia-Pacific community.

From : Communities>>Regulatory Open Forum
Hello Anon, In the version, I usually put the last year or the year generally recognised, e.g. ISO 14971 being 2007.  Then for the publication date, I do put the latest version when published so would be April 2010.  Because of the way standards are amended and revised, it can be quite difficult to determine what to put on the cover sheet.  I would also rely a bit on the Recognized Standards list the FDA publishes:  https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfStandards/search.cfm  to list [More]

From : Communities>>Regulatory Open Forum
Hello Jose, To my knowledge, the change of O/O does not trigger a notification that needs to be confirmed, nor does it trigger a review of enforcement history.  The change of ownership and O/O is merely an administrative update that gives FDA both current information and a history of changes.  Of course, if there are known red flags with any of the involved organizations, changes can be scrutinized. Regards, James ------------------------------ James Bonds J.D. Director Regulatory Affairs Atlanta [More]

From : Communities>>Regulatory Open Forum
Thank you Dinar! ------------------------------ MARIA GUDIEL Brea CA United States ------------------------------

From : Communities>>Regulatory Open Forum
Thank you Richard! ------------------------------ MARIA GUDIEL Brea CA United States ------------------------------

From : Communities>>Regulatory Open Forum
The short answer is "yes" provided that the development cell bank was the source for the GMP bank and is comparable in terms of performance. However, the devil is in details and you need to evaluate "comparability" carefully between the development bank and the GMP bank with respect to the characterization data you plan to use for, e.g., to support GMP bank for production, etc. Two ICH guidance documents are useful to look at, Q7 Table 1 and Q5D. The US FDA generally follows ICH guidance but EMA [More]

From : Communities>>Regulatory Open Forum
This message was posted by a user wishing to remain anonymous Dear RAPS members, I am preparing a submission for a device that has no special controls and we have identified the following standards to name a few. 62304-  ANSI AAMI IEC   62304:2006/A1:2016 62366-1:2015-  Medical Devices - Part 1: Application Of Usability Engineering To Medical Devices 14971- Medical Devices - Applications Of Risk Management To Medical Devices I am trying to see what approach will be good. Should I prepare a DOC or [More]

From : Communities>>Regulatory Open Forum
This message was posted by a user wishing to remain anonymous Have you looked into PRA Health Sciences?

From : Communities>>Regulatory Open Forum
Hi All, Always appreciate and respect the great advice that comes through this forum: The scope of my question is CE Mark of a Class IIa medical device system under the MDD (and then eventually MDR): We have Class I devices which will be CE Marked through self-certification. These devices can be used with other CE marked products (not owned by us). One of which is not CE Marked as a medical device (conformity to machinery and low voltage directives). In terms of what we consider this vendor, what [More]

From : Communities>>Regulatory Open Forum
This message was posted by a user wishing to remain anonymous I'd recommend a statement that you are using these standards as general use. A Declaration of Conformity allows you to submit less testing information, but FDA still may request it. In the case of the standards you mentioned, FDA will require that information (e.g. software documentation, risk management, etc). So I would not bother with the DoC as you still have to submit all that material. Here was a nice thread discussing the topic [More]

From : Communities>>Regulatory Open Forum
Hello,  I can see many unapproved combinations of Minoxidil as topical solution like minoxidil+ Azelaic Acid; Minoxidil + Finasteride; Minoxdil+ niacin+retinol+caffeine that are available online for sale in US but these drug products are not approved by FDA as visble from USFDA website.  Can anyone explain that is there any mechanism or guideline to allows to sell such unapproved drug products online in US and also in EU? Or is this totally illegal practice?  Thanks Ankur RAC

From : Communities>>Regulatory Open Forum
Hi, Ankur - Some may be "legal," others not. It's a big industry, and it is fair to be cynical. Combination products for sale that have not been approved-as the combination-by FDA are just that, unapproved drugs. I assume you checked for the approval status in FDA's "Orange Book" (https://www.accessdata.fda.gov/scripts/cder/ob/index.cfm). Even if both active pharmaceutical ingredients in a 2-drug mixture were approved separately on their own, it does not mean the combined product is approved for [More]

From : Communities>>Regulatory Open Forum
Hello Anonymous  You will be generating software documents (which is data of a sort), in accordance  with  ANSI-AAMI IEC 62304, and there is output from ISO 14971 which goes into the submission.   I just think DoCs are wasteful busy time and would do as few as possible. Regarding IEC 62366-1, maybe if you want mention it and do a DoC, but if the device  usability  study is not required in a submission don't  put it in there unless asked.  Just my opinion. Biocompatibility if used, is generating test [More]

From : Communities>>Regulatory Open Forum
Hi, Willard - The Product code RHP won't show any 510(k)s because that is not a match for any regulated medical device. You can see the classification in the "Radiation Emitting Electronic Product Codes" page (https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPCD_RH/classification.cfm?PCD=RHP), where it also notes that for this Product Code, there are no applicable standards for these "UV Lamp, Germicidal" products.  If it were a medical device, it might fall under FDA's classification for certain [More]

From : Communities>>Regulatory Open Forum
These are all unapproved new drugs. Many people who have very limited knowledge of our OTC drug system, assume that if it is sold OTC, it is a monographed drug and they can change the formulation. They do not know that there are two types of OTC drugs allowed-compliance with a monograph or NDA. Minoxidil is one and chlorhexidine antiseptic wash is another. ------------------------------ David Steinberg,FRAPS President Steinberg & Associates, Inc. Pompton Plains NJ USA 609-902-8860 -------------- [More]

From : Communities>>Regulatory Open Forum
The only  possible way I can see any of these products being legally marketed in the US without going the OTC NDA route would be if the ingredients  other than Minoxidil are considered "inactive" and have some purpose (other than their active ingredient purposes) in the formulation.  That said, this might work for the last combination in your listing because all of these can and are often used in OTC products as inactive ingredients with understood and current reasons for existing in a formulation [More]

From : Communities>>Regulatory Open Forum
This message was posted by a user wishing to remain anonymous For device-lead drug combination products, is there any difference in the quality (grade) of API used compared to a pure drug product? The cGMP guidance for combination products does not seem to specify, and since drug claims cannot be made on device-lead drug combination products, it was not clear what quality of drug is required. Thank you!

From : Communities>>Regulatory Open Forum
​I doubt FDA would have any willingness to change the requirements or expectations for a drug product based on whether it is in a strictly drug product versus in a combination product.  The fact also that there is not a published allowance for this is further evidence that FDA expects that the drug will meet the requirements as expected for drug products without providing any allowed changes or classes of changes.  Remember, FDA expects that drug products meet specific requirements.  Things like [More]

From : Communities>>Regulatory Open Forum
Hello, I agree with Ginger, when you look at standards there will most likely be an output of documents from following those standards, i.e. risk management file, usability report, all the software documentation.  These would be included in the different sections of the 510(k) so you can claim them as recognised standards you are following.  I have mentioned in previous posts, we take a simple approach for the declaration of conformity to standards that is a small table describing what we are complying, [More]

From : Communities>>Regulatory Open Forum
Good morning, Willard. In the U.S., disinfectants fall under the jurisdiction of both the FDA and EPA.  The agencies have an MOU in place to better define there roles.  Accordingly, devices that are  intended for "trapping, destroying, repelling, or mitigating any pest or any other form of plant or animal life (other than man and other than bacteria, virus, or other microorganism on or in living man or other living animals). . ." are defined as "pesticide devices", under  FIFRA section 2(h),.    Pesticide [More]

From : Communities>>Regulatory Open Forum
These types of products and combinations you mention are all unapproved drugs and unapproved combinations.  Unless the specific combination is approved or listed in an OTC monograph, it is a new drug and requires a NDA to market it.  Minoxidil is a Rx to OTC switch product so it requires a NDA or ANDA to market this drug in the US, even as a OTC drug.  Thus any combination with minoxidil is a new drug. In the past the FDA has also specifically stated that combining different types of products (drug [More]

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.

By Laurie Meehan

SOP revision. It falls somewhere between income tax prep and colonoscopy prep on the likability scale.  So why would you want to read about it?  Maybe you’re hoping someone’s figured out a way to make the process more efficient and less painful.  Maybe we have.

The SWAT Technique

Last month, we worked with a company to revise a set of SOPs using a technique we call SWAT.  (Any edgy appeal that name might have otherwise had will be immediately dulled by its acronym expansion: “SOP Working Analysis Team.”  It’s the best we could do.  Don’t judge.)

The goal of the SWAT technique is to revise the most documents in the least time, while preserving friendships, sobriety, and original hair color.  The heart of SWAT is an immersive, multi-day working session in which participants discuss SOP revisions and incorporate them in real time.  Careful planning, thorough preparation, and commitment from management and participants are keys to keeping the SWAT session productive.

It’s Not For Everyone

Up front, we need to say that SWAT won’t work for every organization.  While the size of the company may not be important, the size of the working team needs to be fairly small.  Also SWAT won’t work for every set of SOPs.  The documents need to be part of a natural grouping – a set of similar procedures – and not a random collection.

But in the right situations, SWAT works very well.  Last month, we conducted a 2-day SWAT session with a client’s QA department to revise a set of 10 auditing SOPs.  We’ve also successfully used the technique with ClinOps teams, for example, to revise sets of monitoring SOPs.

SWAT Planning and Preparation

The SWAT process begins with central planning.  A coordination team selects a logical grouping of SOPs to revise, and assembles a list of specific revisions to be made.  Where it’s not possible to provide specific revisions, instructions and guidelines are developed, such as “remove audit report distribution details” or “update to reflect new file safeguarding practices.”

Each SWAT participant is assigned an SOP from the revision set.  The participant doesn’t need to be the author of record, but must be knowledgeable enough to “represent” the SOP – to learn the document well and understand how it’s similar to the other SOPs in the revision set and in what ways it’s unique.  Based on this understanding, prior to the SWAT session, participants make applicable revisions to their individual documents using the information received from the coordination team.  Participants should also note questions and any open issues appropriate for SWAT discussion using inline comments. 

SWAT Session

The result of the SWAT session is a set of approval-ready SOPs.  The precise structure of the SWAT session to get you there depends on a variety of factors, such as how similar or dissimilar the SOPs are, the extent and complexity of the revisions, and whether subject matter expertise is concentrated or distributed among the group.  But all successful SWAT sessions we’ve conducted share these attributes:

• Duration of 2 to 3 days.  Just long enough to accomplish the aggressive goal, just short enough to keep everyone from diving out the window.
• Real-time revision.  The “SOP of the hour” is projected on a screen while participants sit in front of PCs and update their assigned SOPs accordingly.
• Rigorous facilitation. It’s natural for discussions about company procedures to morph into other topics, such as business strategy or staffing requirements.  Discussion *will* get off topic.  When it does, the facilitator must act quickly to table it.  You can maintain a list of tangent topics on a flip chart, schedule a meeting to discuss the most pressing items, ring a cowbell, blow an air horn, or drop a quarter in the “Diversion Jar” and move on, but keep those conversations out of your SWAT session.  Save the war stories for dinner.
• Commitment to the process.  Scheduling the session is one thing, but remaining dedicated to the session is an act of will. It’s so ridiculously easy for outside work to creep in.  Management and participants must be committed to carving out the time and keeping the barbarians at the gate.
• Of course: Plenty of caffeine and yummy treats.

If you’ve ever worked on SOPs, you know there’s a big difference between done and almost done.  To help ensure you emerge from the SWAT session with the former, time must be allotted for participants to format, polish, and conduct a quality review.  If it’s possible to scare up some on-site administrative support, that could help expedite the process.

SWAT Benefits

When you look on your team’s Outlook calendar and see 3 entire days blocked out, it can seem like an awful lot of time devoted to SOP revision.  But SWAT really doesn’t take any longer than the usual process, it’s just more obvious.  Does SWAT take significantly *less* time?  Mmmm, not sure, but SWAT brings with it other benefits.

SWAT produces a more consistent set of SOPs.  Since every document is compared to every other, it’s easy to notice and correct incidental differences.

SWAT is a cross-training opportunity.  Participants enter SWAT knowing their own SOP very well.  They leave knowing the whole SOP revision set very well.

SWAT gets it done.  Auditors, how many times have you cited facilities for failure to revise their SOPs within the specified window?  It’s not because there’s a willful disregard for SOP procedures.  It’s because, in the real world of work, revising SOPs is seldom prioritized highly enough to get on anyone’s schedule until the end of the revision window encroaches or – oops – has passed.  But schedule a SWAT and they will come. (And because the effort is so visible and so obviously resource-intensive, no one wants to be the one to drop the ball.  Participants come prepared and the resulting documents are the better for it.)

SWAT is a lot more fun.  Revising SOPs on your own is really boring.  Revising them in immersive sessions with colleagues is significantly more enjoyable.  Gallows humor reigns supreme.  Copious amounts of chocolate are consumed.  Air horns are blown in celebration.  Friendships, sobriety, and hair color remain intact.  Participants live to write another day.



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Photo Credit:  Tenaciousme CoffeeArt, under Creative Commons License

What if your favorite movie quotes were written for QA professionals? Would they be as memorable? We think so, but we’ll let you decide.

In the fall of 2015, the internet was rife with tweets sporting the hashtag #ScienceMovieQuotes.  Creative scientists repurposed their favorite movie quotes, gleefully infusing them with nerdy humor for the entertainment of their colleagues.  Such a great idea was just asking to be stolen.  And who are we to resist the siren call of piracy?  So here’s our best attempt at making #QAmovieQuotes go viral.*

…And because the rhymes were just too good, we couldn’t resist…




If you’re feeling creative, here are the American Film Institute’s 100 greatest movie quotes of all time.  Please share your humor!  (Fair warning – we took all the good ones.)

By Laurie Meehan

________________________________________________
* Thanks to Robyn Barnes of MasterControl for this fun idea.

Photo credits

Brando: User:Aggiorna / CC BY-SA-3.0, changes made
Badge: User:Dandvsp / Wikipedia Commons / CC BY-SA-3.0
Nicholson: User:Nikita~commonswiki / CC BY-SA-2.5, changes made
Shawn: Sam Felder / CC BY-SA-2.5, changes made
Leigh: Trailer Screenshot, A Streetcar Names Desire,1951, Public domain
Freeman: User:FRZ / CC BY-SA-2.5, changes made
Aladdin Chocolates: Hans Lindqvist, 2009, Public domain
Flower: Walt Disney, Bambi, 1942, Public Domain
Doune Castle: Keith Salveson / CC BY-SA-2.0
Bogart: Trailer Screenshot, Casablanca,1942, Public domain
Newman: Warner Bros. Entertainment, Cool Hand Luke, 1967, Public Domain

Year in and year out, protocol deviations are the most common FDA Site Inspection finding. Why does this keep happening?

If you’ve seen FDA’s Inspectional Observation Summaries, you know that in 2015 the most frequently cited violation in clinical research by far was “failure to conduct research in accordance with the investigational plan.”  Do you know this finding also topped the list the year before that?  And the year before that?  In fact, deviating from the protocol has been the most common observation every year for the last decade.

Why does this keep happening?



The Nature of Protocols
This will come as a surprise to no one: not all protocols are well written.  Important procedures can be hidden in the most obscure places.  Charts depicting Time and Events Schedules are famous for carrying dozens of footnotes that appear nowhere else in the protocol, yet convey important study procedures.   For instance, a pre-dosing column may include a footnote that provides a timeframe for performing a physical exam; a post-dosing footnote might specify the interval at which vitals must be taken.   Failing to follow study procedures compromises subject safety and data integrity; FDA won’t care whether the procedures were in big bold italics or 7-point font.

This, too, may come as no surprise, but not all protocols are error-free.   Information in charts may not match the narrative.  Procedures in Section A may conflict with procedures in Section B.  When the FDA investigator spots an inconsistency, you’ll be asked which of the two conflicting procedures you followed and why.  If you performed procedure A only because you didn’t even notice there was a B, it will be clear you didn’t read the protocol as thoroughly as you needed to.  The FDA investigator may become concerned that your study execution differed from the sponsor’s intention.  This is not a concern you want to trigger.

For these reasons, it’s imperative that study staff read and understand the protocol.  Study team members need to ask questions about anything they’re unsure of, seek clarification on protocol inconsistencies, and get responses that satisfy before starting the study.   A PowerPoint overview is not sufficient training.

One more irksome attribute of protocols that can make them difficult to follow -- they change.  While most study sites allocate time and resources for initial protocol training, many lack a plan for training staff on protocol amendments.   A disproportionate number of protocol deviations occur in amended procedures, and it’s often because staff members have been insufficiently trained on them.  (And when you do train on protocol amendments, don’t forget to document it.)

Deviation Temptation
A protocol is not a suggestion; PIs cannot substitute their own judgment for prescribed procedures, no matter how well-intentioned the departure.  The protocol for a psoriasis study might call for the PI to perform a series of punch biopsies, very invasive procedures.  After the first biopsy, an empathetic PI might be tempted to skip a second if he observes the plaque is clearing up; the drug is working.  But this would be a protocol deviation.  The protocol for another study might preclude the use of a particular drug, even though the drug is routinely used throughout the practice to treat a symptom that a study participant is exhibiting.  But the study protocol trumps standard of care; prescribing the drug would be a protocol deviation.

A PI who feels she must deviate from the protocol for some reason must obtain prior approval, since failure to follow the protocol can jeopardize the reliability of the study data, if not subject rights and safety.



Deviations Happen
So you’ve thoroughly read the protocol, you’ve asked your questions and received the necessary clarifications, you’ve trained your staff on the protocol and its amendments, and you do your best to follow them.

Despite all your preparation and vigilance, protocol deviations happen.  They just do.  And when they do, here are two don'ts.

(1) Don’t panic.

(2) Don’t let an FDA investigator find them first.
Take the time to fully document any protocol deviations.  Be sure to record why they happened, how they were corrected, and what was submitted to the IRB.

[Note: IRBs have different requirements about what types of protocol deviations should be communicated.  Out-of-window visits are common and are frequently considered too minor to report.  But nothing’s black and white.  If the missed visit resulted in missed doses, that would probably change the calculus. The PI needs to determine whether to notify the IRB, and if no submission is thought necessary, it’s a good idea to document why not.]

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

You know you need a computer systems audit, but that’s literally the extent of what you know.
Has this ever been you?

Yes, you use computers on a daily basis, and you may even use the system that needs to be audited. But you don’t spend your day thinking about where all the system components are located, how services and software are combined, and what Part 11 requirements apply. Terms like “cloud computing” make you feel slightly queasy. You’d rather get a root canal than discuss “distributed processing.” Your expertise is in manufacturing. Or clinical research. Or non-clinical lab operations. And somehow it’s your job to make sure an effective and properly-sized system audit is conducted. Great.



Yet your Quality Assurance colleagues -- whether they’re from your internal QA department or an external compliance company -- need your input. They need to understand what software is being purchased, what services are being contracted, how and where components of the system are being implemented, and how the system will be used.

The good news is that the QA auditors can help you. They know that FDA favors a risk-based approach to validation and Part 11 implementation, and they even know what that means. They love to talk about configuration management and change procedures. They love gathering evidence that demonstrates your system works correctly and is in a state of control, and they know what rocks they should look under to find and fix vulnerabilities.

What follows are examples of the types of information you need to convey to QA – and that they should be asking you about – to properly size and scope an audit.

How do You Plan to Use the System?

Suppose you need to audit the supplier of a new Document Management System. The first thing an auditor would need to understand is how you plan to use the system. How mission critical are the documents you’re looking to store?  Are they covered under regulatory scope?  Maybe you plan to use the system as a collaboration environment for developing new SOPs. That would require a relatively low level of scrutiny, especially if you only plan to print out the finalized documents for wet ink signature. (As a point of comparison, if you plan to use the system to finalize SOP approval, the auditor would need to check that Part 11 requirements for electronic signatures are properly implemented.) What if the Document Management System will be housing critical GxP documents, such as Trial Master Files, Master Schedule Sheets, or Master Batch Records? In these cases, the validation would have to be far more thorough, and Part 11 electronic record features, such as audit trails and archiving functionality, would have to be implemented and verified.

Here’s another “use” example. Similar to the term “Document Management System,” the term “Analytics System” does not tell the whole story. From a business perspective, study start up (SSU) metrics may be vital for sponsors and CROs to collect and analyze. But since they have no regulatory impact, the FDA would not require an SSU analytics system to be validated. (That doesn’t necessarily mean you might not want to, though.) On the other hand, a system that performs statistical analysis on study data for regulatory submission is about as critical as it gets, and would require thorough validation and Part 11 implementation. Other analytics systems, such as dashboards that pull data from critical systems, might fall somewhere between these two extremes.

What is the Vendor Providing? And How? And Where?

If you need to audit a complex system, the questions QA will ask you will go beyond system use. The auditors will need to understand the combination of software and services the vendor is providing, and where the software and data reside.

• Does the software and data reside internally at your company or does the vendor provide a hosting service?
  If the vendor is hosting, the auditor needs to tour the facilities and review SOPs and records to evaluate physical security, staff training, environmental controls, backup procedures, disaster recovery plans, data retention, computer infrastructure, and change control.
  
  
• Does the hosting vendor own its own servers or does it, in turn, outsource that function to a 3rd party hosting company, (possibly even in the cloud)?
  If the hosting is outsourced, ideally an auditor would be able to visit the hosting site. Failing that, the auditor would ask questions about the vendor’s qualification processes and review SOPs that govern vendor selection/management procedures. If the vendor outsources other services beyond hosting, those services might need to be considered, as well.
  
  
• Is the vendor providing any other services?
  Many EDC vendors will provide study-specific services such as screen development and data entry validation edits. Auditors would need to review SOPs for providing these services and understand how the vendor tests and manages modifications to these components as the study proceeds.
  Sometimes computer systems vendors provide ancillary services, such as help desk functions and user account management. That would mean additional SOPs and training records for the auditor to look through.

Other Considerations

There are many. For example, where are you in the product life cycle? You ask different questions about a new system than you would about one that has been operating for a few years. Is the product Commercial off-the-shelf (COTS) or highly customized? COTS systems vendors often have their own validation package which auditors would review, and then ensure proper operation in the sponsor/CRO’s specific environment. A highly customized or custom-built system would require a more extensive validation process.


The Take Away

CSV/Part 11 audits will never be standardized, cookie cutter type activities; there are simply too many factors -- in too many combinations -- to consider. You want your QA efforts to be worth the money you spend and be able to answer the questions FDA says you need to be asking. If you’re unsure how to do that, that’s ok. Other people know, as long as you can help them understand how you plan to use the system, what software and services are being supplied, and how components of the system are being implemented.

In case you missed it, our previous post was Notes 2 Fix Your Notes 2 File.
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Many thinks to Lisa Olson for sharing her insights with me.

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.

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