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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.

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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
Yes, I think there were some previous posts where people uploaded Word versions you can get; just need to look around a little. ------------------------------ Richard Vincins RAC Vice President Global Regulatory Affairs ------------------------------

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
From a clinical perspective, nothing will make your medical device "safe" as this word is defined in a dictionary.  Different jurisdictions will adopt what are essentially legal definitions of this word. Devices that meet this definition are "safe" only within the scope of that definition, which is more than just the words, but also includes the process the regulatory agency follows to determine whether the device meets that definition.  Two different jurisdictions may adopt the same literal definition, [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
Yes, exactly i asked same

From : Communities>>Regulatory Open Forum
This message was posted by a user wishing to remain anonymous Why not use Adobe to fill out the form?  You will need it to compile the submission anyway.

From : Communities>>Regulatory Open Forum
Hi Annie, I knew before that I wouldn't be able to attend to the webcast, so I did not register for it. But I am very curious on Dr. Akras insights. Is it possible to view a recording of it? Thanks, Britta ------------------------------ Britta Cyron Bochum Germany ------------------------------

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
I disagree with Richard. I just had a conversation with the COVID-19 hotline (11:45 am, May 7) and asked about this issue after having read an update from the FDA that said UDIs for EUA devices are waived and GMPs are under limited enforcement. The person I spoke with said the update is correct and that UDIs are waived for EUA devices.  Feel free to contact me if you have any questions.  Bob Bard ------------------------------ Robert Bard JD, RAC [Managing Director] South Lyon MI United States - [More]

From : Communities>>Regulatory Open Forum
Hi everyone, As currently drafted,  the 2020 Chinese Pharmacopeia, the benchmark publication on the safety and efficacy of pharmaceuticals legally available in China, includes 319 new entries. The publication includes more than 5,500 traditional Chinese and Western medicines. The official compendium of the standards of purity, description, test, dosage, precaution, storage, and the strength for each drug legally marketed in China is published by the Chinese Pharmacopoeia Commission. It is designed [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
This message was posted by a user wishing to remain anonymous When this was first issued we printed it out, filled in the answers with careful handwriting and then scanned it back in - which seemed to be perfectly acceptable. Since then we've converted their form to a fillable PDF.​

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
Bob, I stand corrected; if you confirmed with FDA that is good.  From what I was reading and seeing (I must have missed that update) there was nothing addressing UDI or no UDI.for EUA products.  (Personally I am a bit surprised at this since the whole concept of UDI is traceability and they waive this for emergency use products - when there is an issue this is where UDI becomes so important.  Shrugs.) ------------------------------ Richard Vincins RAC Vice President Global Regulatory Affairs --- [More]

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 Richard, Yesterday, I received a follow up from the Hotline (CDRH-EUA-Templates ) to my query. I was reminded that the waiver to good manufacturing practice and labeling requirements were included in the individual authorization letter. The person responding to my question concerning the UDI requirement provided the following: UDI is not specifically noted; however we are not enforcing UDI during the emergency. The specific authorization letter I was reviewing was 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
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
Hi @Britta Cyron , Thanks for your question. Let me connect with m​y RAPS colleagues on this to get you an answer and then I will follow-up with you directly. Best, Annie ------------------------------ Annie O'Brien Community Manager Regulatory Affairs Professional Society regex@raps.org ------------------------------

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
Thank you for posting this here Annie as the webcast was excellent (as would be expected from Dr. Akra haha) - but really it was great to have this publicly available as there was nice information about the EU MDR conveyed. ------------------------------ Richard Vincins RAC Vice President Global Regulatory Affairs ------------------------------

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]

Is data integrity music to your ears?  Ours, too!

ALCOA, GAMP, Part 11, GIGO, we cover it all.
(Sung to the tune of Simon and Garfunkel's "The Sound of Silence.")

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.




____________________
*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.

_______________________________
* 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

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.]

_______________________________________________________________

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.

__________________________________________________________________________
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

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.

Protocol trumps practice. This principle seems clear enough, but complying with it is not always as straight-forward as it sounds. Years of practicing medicine has reinforced the way a physician responds to medical situations. But do these responses run counter to the investigational plan? Can a site’s commitment to standard of care affect its ability to meet enrollment targets?


There’s a lot to consider.



What’s Your Standard of Care?
When deciding whether or not to conduct a particular study, a PI needs to verify that the protocol is aligned with practice norms. For example, an early phase trial might exclude a medication that is part of a practice’s routine therapy. Is the study placebo-controlled? Does it feature a specific comparator drug? Will it include a washout period? Any of these elements could present enrollment challenges or preclude a site from accepting a study at all. Responsible sites want to make thoughtful decisions about study suitability; they want to provide realistic enrollment estimates. Sponsors want this too, and can help sites do both these things by providing them a sufficient level of detail about protocol procedures as early as possible.


The Road to Deviations is Often Paved with Good Intentions
Therapeutic misconception – a well-documented phenomenon in clinical research – occurs when a study participant “fails to appreciate the distinction between the imperatives of clinical research and of ordinary treatment.”* Study participants are not alone in this. Researchers blur the distinction themselves when they conduct procedures that are consistent with clinical care but deviate from the protocol. This may be particularly true for PIs who recruit participants from their own practices. An endocrinologist might ordinarily reduce dosage for a particularly diminutive patient. A pulmonologist would often skip a scheduled chest x-ray she felt wasn’t needed to avoid exposing her patient to unnecessary radiation. An orthopedic surgeon may decide his patient needs more recovery time than usual before attempting her first walk. In a clinical care setting, these decisions are sound, made in an individual patient’s best interest. In a clinical trial, if they differ from the investigational plan and haven’t been approved by the Sponsor, they’re protocol deviations.**

It May be Par for the Course, But It's Still an AE
Specialists who have experience treating particular conditions are also familiar with the complications that ordinarily accompany them. A nephrologist, for instance, knows that a patient with end-stage renal disease frequently experiences bloat from a buildup of fluid between dialysis sessions. Though useful for a doctor treating patients, this knowledge can actually work against a doctor running a trial. How? A PI may fail to report a stomach ache as an AE because it’s so typical, so expected. “Bloat is common for renal patients. If I recorded every GI incident, I’d be recording AEs all day.” At its surface, this PI’s argument sounds reasonable, but what if the study drug itself is contributing to the participant’s discomfort? In order to assess the drug’s gastrointestinal effect, the PI must document the frequency and severity of all GI events.

Lab values that are either above or below normal range are also prime candidates for AE underreporting. “Of course the participant’s liver enzyme is high – we’re testing a cholesterol drug.”

The Importance of Study Oversight
Any GCP course worth its registration fee will discuss the distinction between standard of care and the study protocol. In practice, the distinction is not always as obvious as training sessions might suggest. This is where well-trained CRAs come in. As site monitors, CRAs are in a position to catch deviations that result from lapses into standard of care. Reading through progress notes, a monitor can ensure that any untoward medical event has been reported as an Adverse Event. They can verify that procedures conducted by the PI and site staff are compliant with the protocol. Then, by reviewing which types of data must be collected and emphasizing the importance of following certain protocol procedures, monitors can take the opportunity to re-educate study personnel and help them avoid these common pitfalls.

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* Lidz CW, Appelbaum PS (2002) The therapeutic misconception: problems and solutions. Med Care 40: V55-V63.

**Andrew Snyder of the HealthEast Care System wrote a thoughtful piece describing the compatibilities that do exist between clinical care and clinical research. His arguments provide a useful counterpoint to the issues we’re raising here. https://firstclinical.com/journal/2017/1707_Research_vs_Care.pdf

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

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