Attorney General Eric Holder released the following statement Monday regarding the shooting incident that took place Saturday afternoon in Ferguson, Missouri

Attorney General Eric Holder released the following statement Thursday following his meeting earlier today with President Obama to discuss the latest developments in Ferguson, Missouri

A Puerto Rico businessman pleaded guilty today to bribing Puerto Rico Superior Court Judge Manuel Acevedo-Hernandez, who presided over the businessman’s vehicular homicide trial and acquitted him of all charges

The Justice Department announced today that it has entered into a settlement agreement with the Louisiana Supreme Court that will resolve the department’s investigation of the court’s policies, practices and procedures for evaluating bar applicants with mental health disabilities. The department’s investigation found that during the Louisiana bar admissions process licensing entities based recommendations about bar admission on mental health diagnosis and treatment rather than conduct that would warrant denial of admission to the bar

Today, the Justice Department asked a federal court to dismiss its case involving Oakley Training School in Raymond, Mississippi, because the state of Mississippi and the Division of Youth Services have significantly improved conditions for confined youth at Oakley. The reforms, implemented under a consent decree, resulted in increased protections to prevent harm to youth, improved suicide prevention practices, improved medical, dental and mental healthcare, increased rehabilitative services and improved special educational services

The former chief executive officer of Hanover Corporation was sentenced today to serve 14 years in prison, to be followed by three years of supervised release and ordered to pay $14,784,983.75 in restitution for orchestrating an $18 million Ponzi scheme

The following statement was released Sunday by Justice Department spokesman Brian Fallon concerning the federal civil rights investigation into the shooting of Michael Brown in Ferguson, Missouri

A federal court has permanently barred William Naes of St. Charles, Missouri, from preparing federal tax returns for others, the Justice Department announced today. The permanent injunction order, to which Naes consented, was entered by U.S. District Judge E. Richard Webber of the U.S. District Court for the Eastern District of Missouri

Thank you, Carlie for that kind introduction and for hosting this important gathering along with U.S. Attorneys Judge Leonardo from the District of Arizona, John Walsh from the District of Colorado, and Damon Martinez from the District of New Mexico.

Today, the Justice Department asked a federal court to dismiss the injunction to address civil rights violations at Saint Elizabeths Hospital in Washington, D.C., because the District of Columbia and the Department of Behavioral Health have significantly improved the care and treatment of persons confined to Saint Elizabeths Hospital. Saint Elizabeths is the district’s facility for treating individuals with mental health conditions. The reforms, which were implemented following requirements under a court order, have ensured that persons at Saint Elizabeths Hospital are discharged to the community with adequate supports to live in integrated settings. Further, the reforms resulted in important improvements in integrated treatment planning, psychological and psychiatric services, nursing care and protection from assault.

Today, the United States won court approval of a settlement agreement to reform the ways in which the Portland Oregon Police Bureau (“PPB”) interacts with individuals with actual or perceived mental illness. The agreement was entered jointly by the United States and the city of Portland, Oregon, with the approval of the Albina Ministerial Alliance Coalition for Justice and Police Reform (“AMA Coalition”) and Portland Police Association (“PPA”). The agreement addresses constitutional claims in a civil action filed by the United States pursuant to the Violent Crime Control and Law Enforcement Act of 1994. In today’s order, the court approved the agreement with the requirement that the parties appear for periodic hearings to provide the court progress on implementation of the agreement.

Acting Assistant Attorney General Molly Moran for the Civil Rights Division and United States Attorney Bill Nettles announced today that Reginald Wayne Miller, of Marion, South Carolina, has entered a guilty plea in federal court in Florence to fraud in foreign labor contracting. Additionally, Miller entered a guilty plea to visa fraud and wage and hour violations. United States District Judge R. Bryan Harwell of Florence accepted the guilty plea and will impose sentence after he has reviewed the presentence report which will be prepared by the U.S. probation office.

A federal court has permanently barred a Rancho Santa Margarita, California, man from promoting and selling an alleged nationwide tax scheme that involved using welfare benefit plans to unlawfully increase and accelerate tax deductions and avoid income taxes.

A federal court in New Orleans has permanently barred Shawanda Nevers, of La Place, Louisiana, from preparing federal income tax returns for others, the Justice Department announced today.

The Department of Justice and the Corporation for National and Community Service (CNCS), which administers AmeriCorps national service programs, has awarded $1.8 million in grants to increase the effective and efficient adjudication of immigration proceedings involving certain children who have crossed the U.S. border without a parent or legal guardian.

A federal court has permanently barred Sea Nine Associates Inc. from promoting and selling an alleged nationwide tax scheme that involved using welfare benefit plans to unlawfully increase and accelerate tax deductions and avoid income taxes.

A federal district judge in the U.S. District Court for the Middle District of Florida has permanently barred Jeanne Covington, of Tampa, Florida, and her company, Jeanne’s Tax Preparation and Bookkeeping Inc., from preparing federal income tax returns for others.

Preet Bharara, the United States Attorney for the Southern District of New York, Diego Rodriguez, the Assistant Director-in-Charge of the New York Field Office of the Federal Bureau of Investigation (“FBI”), and Philip R

These are exciting times for Vapotherm Inc. (VAPO) whose share price has almost doubled in value since the beginning of this year.

The following are some of the stocks in the healthcare sector that touched a high yesterday. Will the rally continue?

The Health Impact Project’s toolkit contains resources that help communities, agencies, and other organizations take action to improve public health. The toolkit offers a collection of health impact assessments, guides, and other research to support policymakers’ efforts to consider health when making decisions across sectors, such as housing, planning, and education.

It’s that time of year again when we pause to reflect on the state of the industry – and there’s more to focus on in biopharma today than just the drug pricing debate. As I described last year, we host

The post Our 2019 Year In Review: Macro, Biotech, and Atlas appeared first on LifeSciVC.

M&A is an omnipresent reality in the biopharma industry, from Big Pharma mega-mergers to smaller acquisitions of emerging startups. We’ve recently witnessed several large M&A transactions get closed or announced, including BMS-Celgene, Takeda-Shire, and AbbVie-Allergan; according to BMO Capital Markets

The post BioPharma M&A Drives More Efficient Resource Allocation appeared first on LifeSciVC.

This blog was written by Josh Brumm, CEO of Dyne Therapeutics, as part of the From The Trenches feature of LifeSciVC. I stood in front of 15 skeptical parents and prepared to sell them on an improbable mission. They had

The post Ordinary People Achieving The Extraordinary: Lessons In Leadership From The Court To The C-suite appeared first on LifeSciVC.

Emport LLC is pleased to introduce new training programs and materials to augment its food safety and allergen control portfolio.

What can small sponsors do to secure the outsourcing resources they need as large CROs form strategic alliances with Big Pharma?

Partenships between large pharmaceutical companies and large CROs have become the norm.  The advantages for sponsor companies include shared risk, knowledge transfer, dedicated resources, shorter time to market, and the ability to implement the massive data integration that clinical development requires.  Strategic alliances are arguably as advantageous for their outsourcing partners, providing a steady pipeline of work that’s larger in scope and longer in duration than is typical under traditional arrangements.



Strategic Partnerships in Big Pharma: Implications for the Rest
Advantages for one segment of the industry can introduce disadvantages for another.  Alliances among the large players increase competition for top-drawer CRO resources. Smaller sponsors may find it more difficult to receive the quality of service and level of commitment they might otherwise expect.  A large CRO is likely to assign their most talented personnel to projects associated with their strategic partners.  And if a partner study were to run into trouble, it would be hard to fault a CRO for pulling experienced staff members off a smaller project in order to help out with the big client.  Though a reputable CRO wouldn’t jeopardize the relationship with the smaller client, their responsiveness to routine requests might suffer.  It might take longer to get a question answered, receive requested documentation, making the job of vendor oversight difficult.

Though selecting a large, well-established CRO at the outset may have seemed like the safe bet, what do you do if you’re a small sponsor or biotech start-up who is dissatisfied with the level of service you’re receiving?

“Let’s Bring It In-house.”
Put off by a negative experience, many companies decide to curtail outsourcing, and bring functions like monitoring and project management in-house.

This response is understandable, but it rarely goes well.  There’s good reason to outsource study functions to a CRO, especially if you’re small, or new, or both.  Mid-study is a terrible time to realize you’re in over your head.  You may find it difficult to contract with the service providers you want in the timeframe you need them.  Services you would have preferred be performed by a single company may now have to be farmed out piecemeal, which has the overhead of multiple contracts and makes vendor oversight more difficult to manage.  You don’t have time to go through a thorough qualification process.  You’re not in a good bargaining position; you’re trying to buy a new car after they’ve towed away your old one.  And now you have to rely on your new service provider(s) – the ones who may not be your first choice, whom you had to choose in haste, whom you didn’t get to thoroughly vet – to jump in midstream and pick up a study that is already in trouble.

Options for Small Sponsors and Start-ups
So what’s the answer?  You have several good options we’ve seen work well for smaller organizations.

(1) Go smaller.  Look beyond traditional outsourcing choices and consider selecting smaller vendors who may well be in a better position to focus on individual projects and give priority to shorter term engagements.  After all, a project that’s small to a big CRO will be comparatively big to a small CRO.

(2) Go long-term.  Consider establishing strategic partnerships of your own.   Doing so would increase the expertise and technology to which you’d have ready access, and could extend your global reach.

(3) Go big, but go vigilantly.  There’s a reason companies hire big, reputable CROs.  ‘Big’ means the CRO has an impressive set of resources at its disposal.  ‘Reputable’ means it has a proven record of successfully completing studies, producing reliable data, and preserving subject safety.  Smaller sponsors can still take advantage of everything a big CRO offers if they can commit to conducting very strict vendor oversight.  They need to closely monitor the quality of the work the CRO performs, frequently assess adherence to the many written study plans, and make sure deadlines are being met.  Service contracts should guarantee a certain level of responsiveness (by specifying maximum turn-around times, for example), especially for those requests that enable these oversight activities.


Qualification is Key
While the key to Option 3 is effective vendor management, the key to Options 1 and 2 is effective vendor qualification.  Resources are tight in a small company, so you need to direct them where your exposure is greatest, where they’ll do the most good.  What could be more essential to the success of your study than choosing the right company to conduct it?   Many sponsors conduct on-site vendor audits.  That’s good.  That’s necessary.  But it’s not sufficient.  To consistently choose the best possible CRO for your study, sponsors need to:

• Formally document and maintain vendor selection criteria and qualification process
• Form selection committees that represent all sides of your business – finance, contracting, operations, finance, QA, data management, pharmacovigilance, biostatistics, etc.
• Conduct on-site audits with well-trained, well-prepared QA auditors
• Track the resulting CAPA activities
• Ensure outstanding issues are resolved before the contract is signed
• Periodically re-evaluate vendors to make sure they can continue to deliver the same level of quality they’ve delivered in the past

Strategic partnerships among large companies have reshaped the research environment for industry players of every size.  Small and mid-sized companies who take the time to review current outsourcing arrangements, assess alternative models, and thoroughly qualify new vendors and partners will fare the best.

Photo Credit: FreeImages.com/Svilen Milev

Q: If Notes to File can be regulatory red flags, should we quit using them?
A: No, and here's why...

Regulatory inspections are often conducted long after the conclusion of the study. When an FDA investigator asks you a question about an anomaly five years after it’s happened, will anyone recall the circumstances well enough to satisfy the regulator’s concerns? You’ll be doing yourself a huge favor if you write NTFs that answer the questions regulators might one day be asking you.



NTFs can be used to effectively explain an irregularity, locate a document, or note a change in procedures. While there are no regulations or guidances that govern NTFs per se, ICH E6(R2) 2.10 states “All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation and verification.” A well-written NTF will not only describe an event, but will document who made the notation and when, why the problem occurred, what was done to fix it, and what changes were made to keep it from happening in the future. That’s a lot, so it’s a good idea to develop an NTF template to remind authors to include these elements.

Example of a poorly written NTF:
Informed Consent for study BH-90210 was revised by the IRB 01/7/2017. Subject 867-5309 was not re-consented at her next study visit, as per IRB instructions.

This NTF does nothing more than document the deficiency.

Improved NTF:
Informed Consent for study BH-90210 was revised by the IRB 01/07/2017 to include lab procedures on Visit 5. IRB instructions required a re-consent for all enrolled subjects at next study visit. Subject 867-5309 was not re-consented at her next (2nd) study visit, but was re-consented at her 3rd visit.

This version of the NTF gives us a little more context and lets us know that the subject was re-consented before the new lab procedures were performed. The oversight was corrected in time to preserve Jenny’s* rights, but we still don’t know why it happened; there’s not enough information to satisfy a regulator that failure to re-consent was not a pervasive problem. What were the site’s re-consenting procedures at the time of this study? Were they being followed? Who do we ask?


Complete NTF Using Template



Since the subject was consented before the additional lab procedures were performed, there was no violation of informed consent regulations. This was an oversight with no ill-effects, not a significant break with procedures. Discussing it at the departmental meeting is an appropriate, proportional response. (Note that if the subject had not been re-consented before the new lab procedures were performed, the site would have been in violation of consent regulations and an NTF would not have been sufficient. Both the IRB and the sponsor would have needed to be informed of the failure to consent.)

A poorly written NTF – one that doesn’t provide enough information, one that identifies a problem but no solution, one that is inadequately standing in for proper record keeping – won’t satisfy a regulator’s concerns. These are the sorts of NTFs that can actually do more harm than good. A well-written NTF, on the other hand, is something your future self will thank you for.

In case you missed it, our last post was about how GMP activities affect GCP study procedures.
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* If you know why Subject 867-5309 goes by “Jenny," one of your friends wore a pink tux with shoulder pads to prom.

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.

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

True or False:

(1) eSource in clinical trials means eliminating the possibility for transcription errors.

(2) Data collected in Electronic Data Capture (EDC) systems is eSource.

Strictly speaking, both statements are false. If that surprises you, it’s probably because many casual uses of the term “eSource” actually differ from the formal definition laid out by FDA. If the participants in any discussion share the same interpretation of “eSource”, or if it’s clear from context how “eSource” is being used, then no harm, no foul. (Contemporary translation: “Meh.”) BUT…and you know where we’re going with this…when a term can be interpreted in multiple ways, there’s always a possibility for miscommunication and cross talk.



FDA Guidance on eSource in Clinical Investigations
FDA defines eSource as *any* data initially recorded in electronic format. That’s a broad definition, one that includes:
     a) equipment-generated data, such as digital imaging and labs
     b) electronic Patient Reported Outcome (ePRO) transmissions
     c) data streams from mobile health devices, such as Apple ResearchKit
     d) data entered directly into an EDC, known as Direct-Data-Entry (DDE) solutions
     e) data entered into an Electronic Health Record (EHR) or electronic Medical Record (EMR) system


Discussion of Direct-Data-Entry (DDE)
DDE systems allow research staff members to use portable devices to enter study data directly into an EDC system. DDEs have been garnering a lot of industry attention of late, and a number of companies offer solutions that offer a DDE data flow. As independent 3rd party auditors, we don’t want to play favorites by mentioning specific systems as examples, but if your company sells or uses a DDE system that you want to highlight, feel free to add a comment below to give it a shout out.

Discussion of EMR/EDC Integration
Not long after finalizing its e-Source guidance, FDA hosted a webinar that encouraged companies to explore direct EMR/EDC integration. While a few industry players have taken up the effort, movement has been slow. One difficulty: generally EMRs are built with healthcare in mind, not clinical research. Secondly, with so many EMR and EDC vendors, ensuring that EMR data from one system is mapped to appropriate EDC fields in another system relies heavily on data standards that are still being defined and need to be implemented on both sides. 

Source Data Verification (SDV)
If data is transmitted directly from the source system to an Electronic Data Collection (EDC) system, SDV is not required, since the source data isn’t being transcribed manually. (Note: other types of Source Data Review (SDR) activities are still necessary, even if SDV isn’t. SDR must be conducted to verify ALCOA-C data principles such as attribution, originality, accuracy, completeness, etc.) Direct transmission from source system to EDC system is the typical pathway for items (a) – (d) above, and so SDV is not required for these types of eSource.


Common Confusions
SDV. Unless there is EMR/EDC integration – Item (e) above – source data from an EMR system needs to be manually transcribed. This is what makes T/F question #1 false. Just because source data originates in an EMR, it does *not* suggest SDV checks are superfluous. You could argue, as many have, that SDV is not a high-value activity and uncovers only a small percent of data error. That argument may well influence how much SDV is conducted, but whenever data is transcribed from original source into an EDC system, SDV is a relevant discussion.

EDC Data. It’s not unusual for someone to refer to data stored in EDCs as eSource. Data stored in EDCs are electronic, and may be source, but only if the EDC is the first place the data is recorded. This is what makes T/F question #2 false.

In Summary
If you’re ever in a discussion about eSource and things start going sideways, it may be time to haul out the formal definition of eSource -- in all its tedious detail -- to make sure everyone is using the term the same way. 

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Image Credit: Paradox by Brett Jordan

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

Guest Blogger: Greg Weilersbacher
Founder & President, Eastlake Quality Consulting

All companies outsource. It’s a humbling fact that you simply can’t do it all yourself. This often has to do with resource allocation; your company may allocate dollars to build and sustain some activities in-house while choosing to contract higher-cost operations to qualified suppliers who already have the expertise and equipment. 

You may outsource the manufacturing of tablets, sterile injectable, or topical dosage form, or the GMP release and stability testing of your product. Once the production and testing is complete, the product may need to be stored under controlled temperature and humidity conditions and then distributed to locations around the globe. The Contract Development and Management Organizations (CDMOs) who execute these critical operations are of paramount importance to your company’s success. Choosing the right suppliers will also help to minimize stress-induced headaches throughout your organization. Here are the top five ways to get the most out of a supplier audit.



1.  Come to the Audit Prepared
This seems obvious. However, more often than not, quality auditors step into the supplier’s lobby without doing their homework. Ask yourself the following questions: Why am I auditing this supplier? Is this supplier new to my company or one that we have used before? If used previously, have I read over the audit observations as well as the supplier’s responses and do I understand them? Which audit observations do I suspect would be the most challenging for the supplier to address and which are most important to my company’s requirements for this product? Have I reviewed previously executed production batch records and testing data and are there issues that need to be resolved? Are their deviations and CAPAs to follow up on?

Your understanding the supplier’s work proposal is of great value in refining the scope of the audit. Ask yourself:  Which of our products may be manufactured and tested here and which strengths (e.g., potency) will be produced? Which equipment is likely to be used? For a tablet production, the equipment train could include balances, blenders, roller compactor, spray dryer, solvent-rated oven, comils, tablet press and tooling, gravity feeder, coating systems, de-duster, weight sorter, metal detector, tablet counter, etc. This list of equipment will assist you in requesting equipment records during the audit. 

2.  Stay On Point
Proper audit planning will help to keep the audit organized and adhere to the audit timeline. In advance of the audit, provide the audit host with a list of the technical, lab, and manufacturing staff you wish to speak with and the records you need to review. A well-organized host will have this available for your review. Stick to your audit agenda. This is critical. The best way to derail your progress is to spend precious time chasing down minor issues while glaring problems get little to no attention. Continually refer back to the audit agenda and remember to keep the content of your audit report in mind while executing the audit.


3.  Know Your Technical Expertise and Limitations
Many auditors have led previous lives in the laboratory or in manufacturing while others started their careers in quality assurance and may have little technical background with regard to equipment, manufacturing processes, GMP utilities and laboratory testing. Know your limitations and if necessary strengthen them by hiring an expert consultant to assist you during the audit.

A common problem area that is at best glossed over and at worst completely ignored during an audit is the CDMO’s compliance with GMP utilities requirements. All too often, this is due to the auditor’s lack of understanding of the operation, inputs and outputs, validation parameters, and periodic testing and maintenance requirements for utilities such as HVAC, clean or pure steam, purified water and WFI systems, autoclaves, clean compressed air, nitrogen and other gases used for operating equipment or used during processing activities in manufacturing. Typically, these areas are also less well understood by the CDMO’s employees and as a result noncompliance abound. 

Some GMP utilities may be connected to the facility’s building management system, while others may be stand-alone equipment. In either case, the CDMO should have records of alarms (e.g., out of specification or out of range conditions), an acknowledgement of each alarm by designated staff members, and documentation of corrective actions. The last item is key. This is where the execution of quality systems tends to fail. Make a point to request documentation of corrective actions for each utility alarm. 

Additionally, purified and WFI water systems along with gases, such as clean compressed air and nitrogen, require periodical sampling/testing at each point-of-use. Verify that the timelines (monthly, quarterly, or annual) for sampling and testing were performed as directed by the CDMO’s procedures. These timelines are typically not well adhered to. A clear understanding of all the operations of the supplier’s GMP utility management process will keep your thoughts clear during the audit and help identify areas that are in need of improvement. 

4.  The Auditor’s Job is to Identify the Good and the Bad (Not to Win the Debate)
An important goal of a supplier audit is to identify the supplier’s strengths and weaknesses and come away from the audit with a compliance assessment that your company can use to make important decisions. It is of no value to your company if the goal of the auditor is to show the supplier how much he or she knows by debating the fine points of compliance. GMP auditors with decades of experience generally avoid this competitive exchange as it is unproductive. Rather, it is more important to the spend the necessary time identifying compliance issues, making them known to the audit host in a professional manner, and taking detailed notes that assist in writing the audit report. Your company’s senior managers need to know the supplier’s good and not-so-good points; detailing all of these provides the greatest value. 

5.  Interview the CDMO's Lab Staff, Manufacturing Operators, and Shipping/Receiving Personnel
CDMO’s quality systems are generally written by managers and directors who have many years of industry experience. It is of utmost importance that staff members who execute these systems understand them if your company’s product is to be manufactured, tested, stored, and distributed in a compliant manner. Request to speak with manufacturing staff members who work on the production floor and are likely to work on your product. Ask them about the process they would follow to conduct lines clearance, charge powders to a blender, operate a spray dryer, use a comil, set-up of a tablet press, inspect tablets, use metal detectors, etc. Compare the information they provide to the CDMO’s SOPs to determine if the staff understands their jobs. Listen for phrases such as “I usually do it this way…” or “it’s a different every time but I typically set up the equipment like this…” These phrases reveal a lack of control and adherence to procedures. 

The Take Away
The audit itself lays the foundation for a relationship with the supplier and the take-away message should address the following questions: Will the supplier work to resolve the issues I’ve identified? Am I confident that the supplier will immediately notify and involve my company’s representatives when deviations occur during production or testing? Do the supplier’s quality systems and records meet my company’s requirements and those of regulatory agencies? How confident am I that the supplier will produce and/or test a quality product that my company can stand behind? Is the supplier simply a pair of hands or are they committed to be my partner in this product’s success? The answers will provide you with a comfort level in making the decision to move forward with the CDMO or to look to the their competition.  

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A version of this article was first published in Outsourced Pharma.

 About the Author
Greg Weilersbacher is the Founder and President of Eastlake Quality Consulting, a GMP consulting firm based in the Southern California area. Over the last 25 years, he has held director and vice president positions leading Quality Assurance, Quality Control, Analytical Chemistry, Materials Management, GMP Facilities, and Product Manufacturing in biotech and pharmaceutical companies. His unique experiences and technical background have led to the manufacture and release of hundreds of solid oral, sterile, and biologic investigational products to clinics in the U.S. and abroad. Email Greg at weilersbacher.greg@gmail.com.

With the COVID-19 impact making itself apparent on a daily basis as the numbers climb and organizations respond, the effects on the pharma and biotech sector also shifts. Yesterday FDA announced a new concentration of agency assets to be focused … Continue reading →

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Antibody tests are meant to recognize a past infection. Many of these have hit the market in recent weeks and are being offered at local clinics. Officials have touted the tests as crucial for reopening the economy and developing public health strategies to contain the virus.

But there are still questions about how accurate they are. And even with a very good test, it's possible to test positive for antibodies even when you don't actually have them. Watch our new video to learn why.

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Through programs like the Small Business Administration’s Paycheck Protection Program and the Federal Reserve’s Main Street Lending Program, the federal government is deploying hundreds of billions of dollars in grants, loans and bond purchases to help businesses amid the coronavirus-sparked economic crisis. Each program comes with different strings, but their basic purpose is to keep workers on the payroll.

We want to know what this means for your workplace. How has your company treated its workers during the crisis? Have you or your colleagues been laid off, furloughed or otherwise affected? Have you seen money used in surprising ways? What do you think we should be reporting on?

We are the only ones reading what you submit. If you would prefer to use an encrypted app, here is what we suggest. Send questions to bailout@propublica.org.

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by Marshall Allen

The links to the viral video “Plandemic” started showing up in my Facebook feed Wednesday. “Very interesting,” one of my friends wrote about it. I saw several subsequent posts about it, and then my brother texted me, “Got a sec?”

My brother is a pastor in Colorado and had someone he respects urge him to watch “Plandemic,” a 26-minute video that promises to reveal the “hidden agenda” behind the COVID-19 pandemic. I called him and he shared his concern: People seem to be taking the conspiracy theories presented in “Plandemic” seriously. He wondered if I could write something up that he could pass along to them, to help people distinguish between sound reporting and conspiracy thinking or propaganda.

So I watched “Plandemic.” I did not find it credible, as I will explain below. YouTube, Facebook and Vimeo have since removed it from their platforms for violating their guidelines. Now it’s available on its own site.

Sensational videos, memes, rants and more about COVID-19 are likely to keep coming. With society polarized and deep distrust of the media, the government and other institutions, such content is a way for bad actors to sow discord, mostly via social media. We saw it with Russia in the 2016 election and we should expect it to continue.

But what surprised me is how easily “Plandemic” sank its hooks into some of my friends. My brother also felt alarmed that his own church members and leaders in other churches might be tempted to buy into it.

The purpose of this column is not to skewer “Plandemic.” My goal is to offer some criteria for sifting through all the content we see every day, so we can tell the difference between fair reporting and something so biased it should not be taken seriously.

Here’s a checklist, some of which I shared with my friends on Facebook, to help interrogate any content — and that includes what we publish at ProPublica.

Is the Presentation One-Sided?

There’s never just one side to a story. I mentioned this point in 2018 when I wrote about my faith and the biblical basis for investigative reporting. One of my favorite Proverbs says, “The first to state his case seems right until another comes and cross-examines him.” So a fair presentation should at least acknowledge opposing points of view.

I didn’t see this in “Plandemic,” so I called the filmmaker, Mikki Willis, who is also the film’s narrator, to ask him whether I had somehow missed the other side of the argument. I had not. “The other side of the argument plays 24/7 on every screen in every airport and on every phone and in every home,” Willis said. “The people are only seeing one side of the story all the time. This is the other side of the story. This is not a piece that’s intended to be perfectly balanced.”

I asked Willis if it was fair to call his film “propaganda,” which the Oxford dictionary defines as “information, especially of a biased or misleading nature, used to promote or publicize a particular political cause or point of view.”

He said he doesn’t feel there’s anything misleading in his film, but otherwise the definition fits. And based on that definition he feels 100% of news reporting is propaganda. “What isn’t propaganda these days?” he asked. “In that sense, what we’re doing is fighting fire with fire.”

Is There an Independent Pursuit of the Truth?

The star of “Plandemic,” medical researcher Judy Mikovits, is controversial. The magazine Science reports that it published and then retracted one of her papers in 2011. A search warrant provided to ProPublica by one of her former attorneys shows she was fired from her position at Whittemore Peterson Institute, a research center in Nevada, in September 2011. Then she allegedly stole notebooks and a laptop computer from the Institute, the search warrant said, leading to an arrest warrant for alleged possession of stolen property and unlawful taking of computer data. She was arrested on Nov. 18, 2011, but denied wrongdoing. The charges were dropped.

But “Plandemic” ignores or brushes past these facts and portrays her as an embattled whistleblower. “So you made a discovery that conflicted with the agreed-upon narrative?” Willis says to Mikovits, introducing her as a victim. “And for that, they did everything in their powers to destroy your life.”

A typical viewer is not going to know the details about Mikovits’ background. But as the primary source of controversial information being presented as fact, it’s worth an online search. The fact-checking site PolitiFact details her arrest and criminal charges. Clearly, there’s more to her story than what’s presented in “Plandemic.” That should give us pause when we assess its credibility.

Is There a Careful Adherence to the Facts?

In “Plandemic,” Willis asks Mikovits about her arrest: “What did they charge you with?”

“Nothing,” she replies. “I was held in jail, with no charges.”

Being charged with a crime is one of those concrete facts that we can check out. Science magazine reported Mikovits’ arrest and felony charge. I also found a civil lawsuit she filed against the Whittemore Peterson Institute in 2014 in the U.S. District Court for the Southern District of California. “Mikovits was arrested on criminal charges…” her complaint says in the case, which was eventually dismissed.

I asked Willis about the apparent discrepancy, where she said in his film that she wasn’t charged, when court documents show that she was charged. After my inquiry, he said he spoke to Mikovits and now feels it is clear that she meant that the charges were dropped.

I tracked down Mikovits and she said what she meant in the film is that there were no charges of any type of wrongdoing that would have led to her being charged with being a fugitive from justice. She admitted that all the controversy has been hard for her to sort out. “I’ve been confused for a decade,” she told me. She said she would try to be more clear in the future when she talks about the criminal charge: “I’ll try to learn to say it differently,” she said.

This underscores the importance of careful verification, and it distinguishes the craft of journalism from other forms of information sharing. People often speak imprecisely when they’re telling their stories. It’s our duty to nail down precisely what they do and do not mean, and verify it independently. If we don’t, we risk undermining their credibility and ours. That’s in part why we at ProPublica and many other journalists often link directly to our underlying source documents, so you can verify the information yourself.

Are Those Accused Allowed to Respond?

Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, is one of the nation’s leaders in the response to the coronavirus. In “Plandemic,” Mikovits accuses Fauci of a cover-up and of paying off people who perpetrate fraud, among other things. PolitiFact found no evidence to support the allegations against Fauci.

Every time I write a story that accuses someone of wrongdoing I call them and urge them to explain the situation from their perspective. This is standard in mainstream journalism. Sometimes I’ve gone to extreme lengths to get comments from someone who will be portrayed unfavorably in my story — traveling to another state and showing up at their office and their home and leaving a note if they are not there to meet me. “Plandemic” doesn’t indicate whether the filmmakers reached out to Fauci for his version of the story. So I asked Willis about it. “We did not,” he told me.

Are All Sources Named and Cited, and if Not, Is the Reason Explained?

All sources should be identified, with their credentials, so viewers can verify their expertise or possible biases. If they can’t be for some reason, then that should be explained. “Plandemic” features unnamed people in medical scrubs, presented as doctors, saying they’re being wrongly pressured to add COVID-19 on people’s death certificates or are not being allowed to use the drug hydroxychloroquine to treat patients. But the speakers are not named, so we can’t really tell who they are, or even if they are doctors at all. That makes it impossible to tell if they are credible.

I asked Willis why he didn’t name those people. He told me he was in a hurry to release the 26-minute version of “Plandemic,” but the doctors will be named in the final version. “We should have done that,” he said.

Does the Work Claim Some Secret Knowledge?

“Plandemic” calls itself a documentary that reveals “the hidden agenda behind COVID-19.” We are in the midst of a global pandemic where few people in the world can figure out what is happening or the right way to respond, let alone agendas. We have almost every journalist in the country writing about this. And if the truth about a conspiracy is out there, many people have an incentive to share it. But “Plandemic” would like us to think it’s presenting some exclusive bit of secret knowledge that is going to get at the real story. That’s not likely.

Plus, to be honest, there were so many conspiratorial details stacked on top of each other in the film I couldn’t keep them straight. When I spoke to Willis I told him I was having a hard time understanding his point. Then I took a stab at what I thought was the main thrust of his argument. “Are you saying that powerful people planned the pandemic and made it happen so they could get rich by making everyone get vaccines?” I asked.

It turns out Willis isn’t sure either. “We’re in the exploratory phase,” he told me. “I don’t know, to be clear, if it’s an intentional or naturally occurring situation. I have no idea.”

Then he went on to say that the pandemic is being politicized and used to take away our civil liberties and leverage other political policies. “Certain forces” have latched onto the situation, he said. “It’s too fishy.”

He had me at, “I have no idea.” That sums it up. This is a vast pandemic and massive catastrophe. Our country wasn’t prepared for it, and the response by our top leaders has been disjointed. We’re restricted to our homes. Many people have lost their jobs and some are afraid or sick or dying. That makes us vulnerable to exploitation by people who will present inaccurate or intellectually dishonest information that promises to tell us the truth.

Perhaps “Plandemic” is guilty of sloppy storytelling, or maybe people really do believe the things they’re saying in the video. Or perhaps they’re being intentionally dishonest, or it’s a biased connecting of the dots rooted in personal and professional grievances. I don’t know because I can’t get inside their heads to judge their motives.

Ultimately, we’re all going to need to be more savvy consumers when it comes to information, no matter how slickly it’s presented. This may be but a signal of what’s to come in the run-up to the 2020 presidential election, when memes and ads of unknown origin come across our social media feeds. There are standards for judging the credibility of the media we take in every day, so let’s apply them.

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It was just confirmed that I'll be teaching in Temple University's RA/QA MS program this spring. Specifically, I'll be teaching the ad-promo course.

If you or anyone you know is interested, please reach out to me for information. The course will be taught out of the Fort Washington campus, but online enrollment is permitted.

Here's the complete schedule of classes for the spring.

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