Water Minister David Littleproud has unveiled a $20 million study into climate change, ecology and hydrology in the Murray-Darling Basin.

As a new year of tertiary education gets underway and Australia recovers from a summer of bushfires, Australian universities have told SBS News there has been increasing interest in their environment courses. Here, three students share their motivations.

A study suggests Australian bushfires were 30 per cent more likely as a result of climate change but there was no clear climate-change driver for local drought.

From cloud brightening to heat-tolerant corals, a study has identified 160 possible interventions that could help protect the Great Barrier Reef.

Australia is ratcheting up pressure on China to look into the health risks associated with wildlife wet markets as the world continues to battle the deadly spread of the coronavirus pandemic.

(MedPage Today) -- Survival rates were significantly higher, though mechanical ventilation-free survival did not differ between hospitalized COVID-19 patients treated with high-dose anakinra (Kineret), an interleukin-1 receptor antagonist, and...

Mass shooters appear to injure and kill more people when the use semiautomatic rifles instead of handguns, other types of rifles, or shotguns, according to a new analysis in the Journal of The American Medical Association. But the research has significant limitations.

The results, if they hold up, are likely to result in many patients getting the medicine, and could upend decades of orthodoxy among cardiologists.

WASHINGTON–(BUSINESS WIRE)–The Association of Clinical Research Organizations (ACRO) applauds Research!America for a recently released survey on the public’s perception of clinical trials....

Researchers in America have been studying famotidine, the active ingredient in Pepcid, as a potential treatment for COVID-19.

Research into coronavirus cases in Shenzhen, China found that men were 2.5 times as likely to exhibit severe symptoms.

The coronavirus pandemic is likely to last as long as two years and will not be properly controlled until two-thirds of the world’s populations have become immune.

“Eradicating youth violence is a priority of this administration and a priority of both these agencies," said Attorney General Holder and Education Secretary Duncan.

Sutro Biopharma Inc.'s (STRO) interim phase I updated clinical data for a dose-escalation study of antibody drug-conjugate STRO-002 in ovarian cancer has been encouraging.

Today's Daily Dose brings you news about the revised FDA decision date for Bristol Myers' CAR T cell therapy for refractory large B-cell lymphoma; Enanta Pharma's primary biliary cholangitis trial results; MacroGenics' anticipated clinical data read-outs and regulatory event for this year and Trovagene's name change.

A study demonstrated Wellmune® may protect intestinal barrier function in adults when faced with stress.

innoVactiv announces today its study supporting the efficacy of InSea2® to beneficially affect post-meal cognition and mental energy has been accepted for publication.

Bergstrom Nutrition, manufacturer of OptiMSM®, a branded form of methylsulfonylmethane (MSM), recently published an article detailing how the small intestine absorbs MSM, particularly in relation to sulfur.

Obese mice with unhealthy lifestyles gain significantly less weight and avoid type 2 diabetes when they receive bacteriophages from the faeces of a lean mouse, according to a new University of Copenhagen study.

Older adults who consumed large amounts of flavonoid-rich foods were two to four times less likely to develop Alzheimer's disease and related dementias over 20 years compared with people whose intake was low, in a study of 2,800 people.

Rousselot, the collagen-based ingredients producer, has revealed a new study which it says provides important answers surrounding the bioavailability of collagen peptides and the modifications they undergo during digestion.

A recent study conducted by researchers at Tufts University suggests that consuming 1.5 ounces of almonds per day, compared to no almond consumption, may help reduce CVD risk factors such as elevated LDL cholesterol levels, and as a result, reduce an individual's healthcare costs associated with treating such conditions.

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.

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

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.

_______________________________________________________________________
* 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.

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

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

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

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

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

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

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

IRB Approvals

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

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


Informed Consent

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


Inclusion/Exclusion Criteria

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

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

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

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

_________________________________________________________________________

*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

Do we ever learn from our past mistakes? For many years we believed that technology was an inevitable force for good. It would give us instant access to a near infinite amount of information and allow us to easily and instantly connect with nearly anyone on earth. What could go wrong? The answer is that...

Click here to continue reading...

The recommended daily allowance of protein may be inadequate to support maintenance of muscle in young women and eating protein from the humble potato can help to maintain muscle, according to research from McMaster University funded by the Alliance for Potato Research & Education.

Researchers working with a group of postmenopausal women found that a technology using casein to encapsulate calcium nanoparticles reduced GI issues compared with more conventional calcium carbonate or calcium citrate supplements.

Combining exercise with a bacterial strain isolated from an Olympic weightlifting gold medalist may synergistically increase endurance compared to training or the probiotic alone, suggests data from a mouse study.

This semester I’ve embarked on an adventure to co-teach a class in the University of Wisconsin-Madison Masters in Biotechnology program. What sold me on the experience was the majority of my responsibility is interacting with second year students on their final major project (essentially their thesis). That said, I will give one lecture, which will be “health