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C2010-659 Fundamentals of Applying SmartCloud Control Desk V1

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C2010-659 exam Dumps Source : Fundamentals of Applying SmartCloud Control Desk V1

Test Code : C2010-659
Test Name : Fundamentals of Applying SmartCloud Control Desk V1
Vendor Name : IBM
: 103 Real Questions

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IBM Fundamentals of Applying SmartCloud

IBM announces New SmartCloud capabilities, Partnership With Nirvanix | killexams.com Real Questions and Pass4sure dumps

IBM has nowadays increased its cloud computing features for enterprise with the launch of recent IBM SmartCloud capabilities. These new offerings include SmartCloud utility features, IBM’s new PaaS for enterprise, a portfolio of hardware and software known as SmartCloud basis, and SmartCloud Ecosystem, which comprises new features for IBM companions and ISVs.

The business plans to help around 200 million clients via the conclusion of 2012.

IBM says that it has ported SAP, ERP and all database functions to its SmartCloud platform. With its new services, it may possibly now automate labor-intensive tasks linked to operating SAP within the cloud, specifically SAP cloning, refreshes and patching. In some circumstances, IBM says the time rate reductions can go from months or weeks to days or hours, counting on the assignment.

also introduced nowadays is a new partnership with Nirvanix, a cloud storage company. Going forward, Nirvanix’s cloud storage know-how should be integrated into IBM’s SmartCloud enterprise storage features, enabling consumers to upload information of any dimension, anyplace in the world, and access them from any place. The storage-as-a-provider providing can support millions of clients, billions of objects and exabytes of records.

in the meantime, IBM’s new platform-as-a-carrier offering, SmartCloud application functions (SCAS) will launch into beta this yr (q4), offering enterprise–grade protection, open Java and go-platform support with no vendor lock-in, and a comprehensive set of utility infrastructure and managed services to allow construction and deployment of purposes to the cloud. It will run on IBM’s SmartCloud commercial enterprise and commercial enterprise+ – the business-type infrastructure-as-a-platform peculiarly designed to run commercial enterprise workloads at dedicated SLAs (provider degree agreements). IBM SmartCloud enterprise+ is attainable within the U.S., and will be deployed international by way of the conclusion of 2012.

ultimately, the new SmartCloud basis family unit of deepest cloud options goals to support agencies promptly design and install inner most cloud environments, and includes SmartCloud Entry, prepackaged private cloud software, plus SmartCloud provisioning and monitoring application.


IBM Evolves from On Demand to SmartCloud | killexams.com Real Questions and Pass4sure dumps

domestic   →   ERP   →   IBM Evolves from On Demand to SmartCloud Posted October 12, 2011 by way of Sean Michael Kerner     remarks

New IBM application features for cloud consist of middleware, DB2, SAP functions and CRM.

IBM (NYSE: IBM) is rolling out a brand new set of SmartCloud capabilities and application, offering new alternatives for companies to move their purposes to a cloud mannequin.

the new offerings consist of the debut of SmartCloud commercial enterprise 2.0, which is a Platform-as-a-provider (PaaS) providing. the brand new SmartCloud will also allow IBM DB2 database-as-a-provider as well other IBM functions. IBM isn't just enabling its cloud for IBM software; the SmartCloud also has a service for SAP ERP functions.

"This announcement takes their cloud capabilities to the next degree," Lauren States, VP and CTO of Cloud Computing at IBM, told InternetNews.com. "We're adding means to the portfolio for software building and deployment in the cloud with SmartCloud application services."

States referred to SmartCloud application services is IBM's PaaS for the commercial enterprise. She mentioned that initially the software services are concentrated on Java applications and transactional database functions with IBM's DB2. there's additionally an SAP purposes carrier that supplies SAP as a packaged app that will also be deployed and administered within the cloud.

"We're beginning with what their core customers use with their know-how and we'll be building that out with other capabilities over time," States noted.

remaining week, Oracle announced its personal public cloud providing, including a database-as-a-carrier providing. States talked about IBM's platform is all about exposing IBM's middleware capabilities as a service. She delivered that programmers who are writing applications for the cloud can simply name the provider, whether or not it's database or a further service, and that they will not have to be troubled concerning the underlying complexity of the stack.

The SmartCloud platform is being delivered on a Linux infrastructure with future plans to expand with windows and IBM's AIX Unix. IBM is the use of KVM and pink Hat as the underlying technology seller platform. The platform can also be used to convey cloud enterprise functions, together with cloud ERP.

IBM is also introducing a SmartCloud basis application portfolio for groups trying to deploy on-premise.

"a lot of customers are just getting started with cloud and that they want to center of attention on the merits of virtualization, management and automation for operational effectivity," States mentioned. "This SmartCloud foundation fills a niche in their on-ramp to the cloud and it could actually set the basis for customers that at last want to get to self-provider, pay-as-you-go infrastructure."

IBM's cloud push is also being prolonged to IBM's latest On Demand hosted consumer base. States referred to that IBM already has a huge application on demand internet hosting business. IBM introduced in April that the plan became to supply On Demand purchasers with cloud capabilities.

"it be their intention to deliver a cloud enabled environment inside their software on demand internet hosting business for those customers that need to leverage that operational effectivity," States spoke of.

IBM additionally announced a collaboration with SugarCRM to make its client relationship management (CRM) items accessible on the IBM SmartCloud business. "valued clientele can now take abilities of advanced CRM solutions, deployable in a count number of minutes, whereas reaching all of the benefits of a non-public cloud ambiance," IBM pointed out in an announcement.

Sean Michael Kerner is a senior editor at InternetNews.com, the information provider of internet.com, the network for technology professionals.


IBM Unveils New ‘DevOps’ CLM tools for the Cloud | killexams.com Real Questions and Pass4sure dumps

IBM the day past unveiled new software and features designed to aid clients streamline the application development lifecycle, or what IBM calls “building operations,” or simply DevOps. As part of the announcement, which turned into made on the annual Rational Collaborate convention in Florida, parts of Rational’s Collaborative Lifecycle administration (CLM) suite may be made obtainable as a DevOps tool hosted in IBM’s SmartCloud.

The CLM suite, which IBM unveiled ultimately 12 months’s Collaborate reveal, is built on IBM’s open construction platform, known as Jazz, and combines three Rational products, together with necessities Composer, crew live performance, and quality manager, in a single suite that IBM says is easier to buy, deploy, and use than separately cobbling the items collectively.

massive Blue yesterday introduced five new CLM products and services as part of its push into DevOps for the cloud. It also introduced new cell capabilities in its CLM suite.

the primary DevOps for the Cloud providing bears an unwieldy name: “IBM Rational answer for Collaborative Lifecycle management on IBM SmartCloud enterprise.” This offering is really a slice of IBM’s SmartCloud commercial enterprise that a consumer can use as a building and examine atmosphere. SmartCloud enterprise, you will remember, is a public infrastructure as a service (IaaS) offering in line with X86 hardware and the Linux OS. SmartCloud enterprise+ helps energy techniques environments, but now not IBM i.

the brand new IBM SmartCloud application functions (SCAS) platform as a service (PaaS) providing that changed into launched in October 2011 additionally has a role in IBM’s cloud-based mostly DevOps plans. IBM sees SCAS (which comprises a Linux OS, WebSphere became, DB2 database, and SAP purposes) giving consumers a place the place they can execute building, build, check, and bring actions.

IBM additionally announced the SmartCloud for executive development and look at various Platform. This providing will give executive organizations a way to access the CLM suite from a scalable, hosted environment. IBM says this offering will conform to the Federal tips safety management Act (FISMA).

additionally playing into the DevOps cloud is SmartCloud continual delivery, which IBM describes as a set of “choicest practice patterns” designed to aid shoppers use CLM tools and IBM’s SmartCloud Provisioning application to manipulate the lifecycle of cloud-based mostly functions. SmartCloud continuous birth was at the beginning unveiled in March, and is at present in beta.

The SmartCloud application efficiency management offering provides purchasers with entry to Tivoli monitoring and management tools for making improvements to the performance of cloud purposes.

On the cell entrance, IBM introduced that its CLM suite can now work with the IBM cell foundation. The cell foundation, if you neglected it, combines three tools, together with the IBM Worklight HTML5 mobile software building and runtime environment; the IBM Endpoint supervisor device; and WebSphere cast iron for integration.

the new business cellular building providing combines CLM, the cellular groundwork, and a couple of other Rational tools, including the new Rational Developer for vigour techniques edition 8.5 liberate (which that you could examine greater about here), Rational Developer for system z 8.5, Rational application Developer 8.5, and the Android SDK and Emulator. IBM says that with the aid of integrating all these items, consumers can expect to velocity up the technique of designing, constructing, checking out, and deploying business cellular apps, and doing so in a cozy and compliant manner.

It’s a wide, wily cloud world obtainable, and IBM is determined to support purchasers reduce throughout the litter and control their cloud utility building activities. “nowadays’s business dilemma is the way to handle both the need for speedy birth and ample handle in the utility building system,” Dr. Kristof Kloeckner, common manager of IBM Rational, says in an announcement. “We need to balance the need for velocity and agility with more suitable governance to manipulate charge and high-quality, obtain regulatory compliance, be sure protection, and have some degree of financial predictability.”

connected studies

IBM Puffs Up New Public, inner most SmartCloud Releases

IBM Ships New Collaborative Lifecycle administration Suite

IBM Consolidates Rational crew live performance items, Simplifies Licensing

IBM Unveils change administration utility for device i

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Fundamentals of Applying SmartCloud Control Desk V1

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From Gold Bar to Joshua Tree | killexams.com real questions and Pass4sure dumps

Warning. A lot of climbing talk ahead.

The next morning, they woke up before 9, ate some cereal with mixed fruits, and headed out with some crash pads. Chad, Brooke, Josh, Wendy and I drove about 30 minutes out into the far desert and parked at the Hidden Valley Picnic Area parking lot (big mistake — there’s a parking lot at the Hidden Valley campsite literally across the street).

Just one of the rock formations at Joshua Tree.

(Side note, I grew up in the high desert. It doesn’t look as stunning or beautiful as this.)

We got lost for a bit and took a long hike around from the west side but eventually found a VERY easy (listed) V1, that was honestly more like a V0 with a very short top out. Maybe they identified the boulder wrong.

Behind us was White Rastafarian. Keep in mind I have no fear doing any V2s at the gym. They’re usually require some technical moves but for the most part, they’re easily doable. White Rastafarian does not follow suit with that trend: the top-out of the boulder is 25 feet high and has a crux about 20 feet up that requires a span from one crack to another.

I ended up being able to make it to a juggy hold about halfway through the problem before I called it quits and decided not to risk injury.

The elusive White Rastafarian. Objects are smaller than they appear — the top of this boulder is 25 feet up!

After this, they headed to Pinhead a smallish boulder about 50 yards or so from White Rastafarian. This had a couple of great routes.

I was able to top out on this route, but due to my poor choice in footing, I slipped and fell, despite grabbing the juggy topout. I got a shallow scrape near my right thumb, and decided forfeit the route in the interest of taping it up and finding something easier. (I now regret not trying the route again after Chad and the others tried it.)

Bandaged up.

I was, however, able to complete the Pinhead Traverse (V0-).

Brooke on the crux of the Pinhead Traverse. Wendy ‘scends the Pinhead Traverse (V0-). Chad using a Double Gaston right before he ‘scends Pinhead.

Chad showed us this route that he found northeast of Pinhead. I’d put the gym grading as a V2 or maybe V2+, but outdoors, it’s likely a V0.

Chad’s V0. Josh and Brooke spotting.

I didn’t try it — I wanted to save my energy for their last planned route for the day: Hobbit Hole Offwidth.

This offwidth boulder was tucked behind some brush and more rocks, and when they got there, Josh and Chad began to scramble up some surrounding rocks in the area. Wendy took a stab at Patina, a friction V1.I honestly had never really tried a friction climb, and the closest I’d seen at a climbing gym were labeled as VHards…

Wendy makes progress on Patina.

Hobbit Hole is obviously an “Offwidth” problem (see this video for reference on what the offwidth climb would look like), but I decided to do a lieback approach. I didn’t want to run the risk of slipping and jamming my body into the crack — I’ve seen 127 Hours and I’d rather not have a similar situation of getting stuck between two rocks.

This problem was a great learning experience, but I’ll just bundle in that lesson into the various other lessons I took away from that day’s climbing:1. Learn to move your feet alongside your hands. This is something that I often teach to newbie climbers and I needed to re-teach myself when climbing outdoors.2. Feel the rock before attempting to finish it. Unlike gym routes, the routes outdoors don’t have colored tape or markings designating where to go next. You can’t see that a hold is a sloper. A shelf or crack may not be consistently juggy throughout. This is also something that I tell new climbers when they send me pictures of a route asking, “What do I do next?” I can only speculate so much. The best remedy is to just go out there and try climbing the rock.3. Be prepared to make risky moves. I think this is a bit hypocritical on my part. On one hand, I promised myself that I wouldn’t injure myself outdoors as to not ruin my trip…but conversely I also realized that I would also prevent myself from performing moves that were either extremely painful, or performed an action that would require a quick recovery rather than a slow, systematic approach. It made me wonder — how do climbers really improve their grade at the gym? Do they just get strong enough (either through repetitive training or focused exercises) to complete higher grades with ease or do they actually experience the pain of making uncomfortable moves and just live with it? I think the right answer here is that it’s a balance of the two, but I’ve been ignoring the latter phenomena — when I reach an uncomfortable move, I often call it quits and then drop down and reassess. Is that what’s selling myself short? Do I fear a moment of pain of which I could possibly work through and see success beyond the horizon?

In the end, I feel like this boils down to a simple principle: remember your fundamentals. Of course, there are problems outdoors that can’t be easily re-created indoors, and there are different risks to take, but I felt that a lot of problem points that emerged when climbing outdoors simply stemmed from losing my cool and remembering my fundamentals even though it seemed like I was presented with a totally different context.

When they left the park that day, Wendy got several messages from her family and informed us that she needed to head back home for an emergency. As a matter of privacy, I’ll spare the details.

When they got home, they relaxed for a bit, and as the evening emerged, they had some pasta, sat around a fire pit, and chatted.A crescent moon appeared in the distance, under the stars, and above the silhouette of the mountains. It was honestly one of the most beautiful scenes I had ever witnessed, and unfortunately I don’t have a picture of it. All I can do is describe it with words and you’ll just have to believe me.

Later, Chad pointed out the International Space Station passing by, which was a bright light that emerged from the west and traveled in a line slowly to the east. Although it looked like nothing more than a steady star moving across the sky, it was exciting and they all chatted about it for quite some time.

Afterwards, Chad brought out his telescope and they got to see Jupiter and some star clusters. Wendy taught me how to take long-exposure night photographs, but the light pollution from town definitely caused the pictures to be less than perfect. I wish I could practice this more, but I didn’t bring a tripod, and also Seattle isn’t exactly primed for clear skies.

Not so great for my first long exposure, but it’ll do for now. Wendy also made us s’mores. Look at that presentation!

We went inside afterwards, then played some Monikers. Chad asked if I could throw together an improv DnD session while Wendy and Vincent called it a night.It was fun, and I wish I could do more sessions like that.

The house before playing Monikers. A bit blurry, but maybe appropriate given the circumstances…

Why the Harper Majority is a Step Back for Science – Let Us Count the Ways | killexams.com real questions and Pass4sure dumps

This is a guest post by David Ng, a science literacy academic at the Michael Smith Laboratories of the University of British Columbia.

In case you missed it, last night saw the Canada election deliver a Conservative majority. It was an interesting and historic vote for a variety of reasons, but the bottom line is that now the Harper government is in a position to do pretty much as it pleases, given its position of majority power in both the House of Commons and the Canadian Senate.

As is the norm for any democratic action, this is good and bad depending on your perspective and ideals. Those who make their homes in the business or economic front generally see the result as a positive; whereas those who value fairness, ethical government practices, and social issues tend to look upon the election as a daunting and frustrating setback. In this mix, however, is the scientific point of view. And speaking as a Canadian scientist, I want to use this space to make the case that all things being considered, this is a fundamentally bad moment in history for Canadian science.

To do this, let’s access how the Harper government (not the “Government of Canada” as it was once officially called) has performed so far (in the science context anyway).

And let’s argue for this in a rational way. They are after all scientific folk. In fact, let’s apply the good old rubric of looking at the claim, providing a reason, and then presenting the evidence for this stance.

First up is their claim: let’s just go with something direct:

The Harper Government is bad for Science.

As for coming up with a reason, it’s actually fairly straightforward. Here, we’ve seen repeated examples that would demonstrate a clear lack of understanding science culture, as well as actions that often undermine the very notion of scientific literacy. Sometimes, you get the sense that science just isn’t important to this government, and on occasion it even feels downright inconsequential.

But, of course, this wordy reason can’t stand on its own verbiage. They need concrete evidence for their claim, and to do this, it’s probably easiest to focus on a number of key points that demonstrate Harper’s modus operandi.

Point 1. The Harper government is not terribly scientifically literate.

There’s a few examples of this (also see point 2), but let’s simply draw attention to the appointment of a Minister of Industry, Science and Technology who waffles on the science of evolution. In case you don’t know his name, it’s Gary Goodyear: and in essence, his role in government is meant to be the primary driver on pushing and representing how science is funded, courted, guided, and basically done in Canada. Although an architect of many a cut to science funding in times that arguably need more scientific innovation (see 4 for more), he was and still is noted as a controversial figure when in 2009, the Globe and Mail asked him to share his stance regarding evolution. To this, he replied, “I’m a Christian, and I don’t think anybody asking a question about my religion is appropriate.”

Now from a scientific point of view, this type of statement is mildly troubling – you would hope that at least the Minister representing science would have more eloquent words to say on this subject. Unfortunately, this wasn’t the case as illustrated with his further comments on the matter when pressed again during a television interview. During this incident, he chose to proclaim his belief in evolution, but continued with this very odd and ludicrous description of what evolution is:

“We are evolving, every year, every decade. That’s a fact. Whether it’s to the intensity of the sun, whether it’s to, as a chiropractor, walking on cement versus anything else, whether it’s running shoes or high heels, of course, they are evolving to their environment.”

2. The Harper government has managed to make Climate Change science an ideological issue.

You’ve actually seen a lot of this already in American politics, but nowadays there’s also a Canadian version. Here’s how it works:

In general, science is fairly particular about the way it is done. The method is built to thrive on objectivity and it is ultimately based on the things they see, record, and analyze. It isn’t perfect, since the concept of a paradigm can exert influence, but the evidence it builds on still has to meet some pretty tough criteria – certainly much more stringent than other epistemologies, or other ways of knowing. Put another way, scientific evidence is not suppose to be swayed by ideological or partisan lines.

Despite this, Harper’s politics have warped the science of climate change into one of partisan debate. All other Canadian political parties take the science at face value, and build from it. Not so with the Conservatives. This is inherently disrespectful to the scientific community, as it suggests that they can make decisions concerning climate change in a place where scientific literacy has no currency, whereby the overwhelming scientific consensus is treated as nothing more than an interesting and suspicious footnote.

As a result, Harper runs the country on the pretense of whether one can trust or distrust the scientific evidence, without actually debating the actual technical strengths and weaknesses of the climate science data currently presented. Harper runs the country based on messages that economically sound promising, but are environmentally unsustainable, and have strong repercussions which conveniently will take form long after he is retired. Above all, he places an emphasis on nurturing a subtle form of climate change denialism and has made it part of the conservative ideology. From a scientist’s point of view, this is probably not the best way to formulate important policies – on “feelings” as oppose to concrete evidence. In essence, they can say that I may not be a betting man: but if I was, I’m pretty sure that the scientific community is the best place to get their odds.

Now, one might argue that this is not Harper’s stance at all. It would appear that the official take would proclaim the government’s official backing of the “fundamentals of climate change science.” However, as always is the case, actions speak louder than words. As evidence of this, you only need to keep track of the Harper’s record on climate change. Since obtaining its first minority government in 2006, the Conservatives have essentially moved away from Canada’s commitment to Kyoto, and has repeatedly undermine climate change talks (to the point of being consistent winners of the “Fossil of the Day” award), part of which involves the continual setting up of disappointing emission targets.

In 2009 the goal was to cut carbon emissions by 20% below 2006 levels by 2020; an equivalent of 3% below 1990 levels by 2020. The goal was later changed in early 2010 to 17% of 2005 levels by 2020; an equivalent of 2.5% above 1990 levels.

The three most populous provinces disagree with the federal government goal and announced more ambitious targets on their jurisdictions. Quebec, Ontario and British Columbia announced respectively 20%, 15% and 14% reduction target below their 1990 levels while Alberta is expecting a 58% increase in emissions. (Wikipedia, April 2011)

More troubling, is that Harper appears to not have any qualms about pushing his agenda in any way possible, and does so in a way that draws clear distinctions between party lines. In particular, is his flagrant misuse of Senate power to go against the democratic passing of a Climate Change Bill (Bill C-311).

Here, a quick lesson in Canadian government procedures might help. Essentially, when Canadian laws or Bills are put on the table, they need to go through a vote in the House of Commons. This is represented by elected members of government, such that the voting here is inherently meant to represent the “will of the people.” However, if passed, the law then needs to go through the Canadian Senate. This level of government is suppose to reflect a place of “sober second thought,” but historically, the Senate very rarely goes against the decisions made in the House of Commons. This is because Senate members are appointed, and therefore in principle are there to still respect the democratic underpinning of the House of Commons’ vote. However, in December 2008, Harper filled 18 vacant Senate spots with Conservative appointments, and has used this Senate majority in undemocratic ways – including the killing of the Climate Change Bill.

Still, there are other ways to force an ideology along: which brings us to point number three.

3. The Harper government has demonstrated a willingness to “muzzle” science.

In 2010, the release of Environment Canada documents showed that new media rules introduced by the Harper Government in 2007, with the aim to control the ability for Federal climate scientists to interact with media, had been responsible for what many of these scientists have called a “muzzling” effect.

“Scientists have noticed a major reduction in the number of requests, particularly from high profile media, who often have same-day deadlines,” said the Environment Canada document. “Media coverage of climate change science, their most high-profile issue, has been reduced by over 80 per cent.”

The analysis reviewed the impact of a new federal communications policy at Environment Canada, which required senior federal scientists to seek permission from the government prior to giving interviews.

The document suggests the new communications policy has practically eliminated senior federal scientists from media coverage of climate-change science issues, leaving them frustrated that the government was trying to “muzzle” them. (Montreal Gazette, March 15, 2010)

This facet of Harper’s strategy is especially troubling. Science, as a whole, is a venture that best works when there is fluidity and an openness in how information is shared. Whether that is within the scientific community in the form of expert peer review, or back and forth between scientists and the general public or the policy makers as a dialogue of civic consequence, there is simply no commendable reason for this form of control. It should be obvious that discussions on Climate Change, which has obvious public importance, things shouldn’t be run like a corporation protecting its secrets and/or hiding information that veers away from the desired message.

4. The Harper Government is out of touch with science culture: scientists are driven by many things, and not always by the industry/business/corporate mentality.

Over the last couple years, we’ve seen examples where the Harper Government has consistently pushed research towards a heavy emphasis for applied sciences and industry, often at the expense of basic science. Whether this is via funding cuts to granting agencies such as the Natural Sciences and Engineering Research Council (a bastion of basic science research), diverting such monies towards projects where business-related objectives are encouraged, or via restructuring of the National Research Council such that industry-related projects are given priorities, there’s definitely a method to his ways. Overall, this indicates a general ignorance of how scientific progress works – that is, it is almost always the discoveries born from basic research that fuel the future innovation necessary for applied benefits. Put another way, if Harper continues on this track to give himself quick political gain, he does so at the expense of future Canadian science. Even a small lull in basic research in the present could result in a significant lull in applied and economic potentials in the future.

As well, this constant patronage towards the business side of science also doesn’t necessarily reflect the intentions of the scientists themselves. Money and economics may be desirable things for scientists, but most often there are other stronger motivations at stake – including an aspiration to bring about positive change in the world, as well as plain old intellectual curiosity.

An example of Harper’s willingness to always give credence to the corporate line, is his Government’s poor handling of the recently diposed Bill C-393. Essentially, this is an episode where bad politics trumped good science. The good science in this case is the fact that there are very effective antiretroviral drug out there, which make HIV/AIDS a treatable disorder. Unfortunately, these are mostly priced too high for individuals in developing countries – countries where unnecessary death from HIV/AIDS is catastrophically high. The bad politics concerns a frustrating series of events that saw a Bill (C-393), designed to fairly and with monitoring facilitate production of generic drugs, get passed in the House of Commons (i.e. democratically given the green light); then was taken to Senate, where it was deliberately stalled for five days, in an atmosphere where misleading information provided by the pharmaceutical industry was being distributed to the Tory Senators; such that it was ultimately killed by default when the new election was called. The fact that the reason for this was ultimately because of the Harper’s Government willingness to patronize Big Pharma is extremely galling, especially when so many lives were literally at stake.

Conclusion

It’s important to note that science culture isn’t the only thing that drives a civil society. However, as a conduit for reasoned discourse and relevant information that affects local and global concerns, it’s obvious that science must not be taken for granted. Based on last night’s election results, they have every reason to worry about the Conservative majority, as the Harper Government has repeatedly demonstrated past activities that not only take science for granted, but treat it with a form of contempt. The Harper government has consistently ignored whatever sound utility the scientific endeavor can provide, and by doing so, has put the future of Canadian science at risk, as well as the elements of society that would have otherwise benefited from it.

In the end, this means that they must watch the actions of this Harper Government more closely; and to be vocal, to be active, and to do their best to hold them to account for their actions. Democracy has given Harper a mandate to govern as he sees fit, and for this there should be an element of respect as well as an element of opportunity. However, Harper should not forget that Canadian democracy is ultimately driven by the people of Canada. For that reason, I will be watching you closely. Scientists will be watching you closely. Canadians will be watching you closely.

David Ng is a science literacy academic at the Michael Smith Laboratories of the University of British Columbia. He has written essays for the Walrus, humour for McSweeney’s, commentary for Boingboing, and is now trying to learn more about Access to Medicine issues at the My Rights Versus Yours Blog. You can follow him on twitter @dnghub. If you’re a Canadian reader, he also encourages you to check out aidsaction.ca to note that almost all conservatives still align themselves with Big Pharma’s stance on Access to Medicine issues. Why not send them an email to make sure they know exactly how you feel?


The Regulatory Strategist Toolbox: Clinical Endpoint Analysis Tools | killexams.com real questions and Pass4sure dumps

One of the critical parts of assembling a product’s “Strategy Playbook” or “Clinical Development Plan” is the researching and planning of clinical endpoints. This article discusses how to research endpoints, including tools to research them, how to organize the information and how to present the intelligence back to the team.

Endpoints are measures intended to reflect the effects (efficacy endpoints) or safety (safety endpoints) of a drug or device. They include assessments of clinical events (e.g., stroke, pulmonary exacerbation, venous thromboembolism), outcomes (e.g., what a final result of treatment long term, mortality, tumor resolution, cure of disease, remission), patient symptoms (e.g., pain, dyspnea, depression), measures of function (e.g., ability to walk or exercise), adverse events or surrogates of these effects or symptoms; clinical outcomes are considered the most reliable endpoint.1 One of the critical parts of the assembling either a product’s “Strategy Playbook” or “Clinical Development Plan” is the researching and planning of endpoints from Phase 1 through 3, including navigating through FDA’s understanding and interpretation of the laws and definitions (Table 1). 

Defining Efficacy Endpoints

Defining efficacy and their measurement through endpoints has been a dynamic process since the US 1962 Kefauver Harris Amendment to the Federal Food, Drug, and Cosmetic Act (FD&C Act), which was the first time a demonstration of efficacy (and endpoints to measure efficacy) was required.2,3 After the amendment, FDA spent the next decade defining, discussing, evolving and defending Sponsors’ lawsuits to arrive at what efficacy expectations should include (and some say the process is still ongoing).4

Prior to the 1962 Kefauver Harris Amendment:

  • efficacy was not clearly defined, safety of the product was relied upon
  • FDA was not involved in the definition of efficacy or claims of efficacy for products
  • companies would define efficacy (and subsequent endpoints) differently for similar products and both companies would claim efficacy of the product
  • companies let the individual physicians define efficacy and endpoints based on their patient population and subject interpretation (which would be combined as case studies into a marketing application resulting in many different endpoints used in the same study).
  • FDA’s definition and struggles to define efficacy served as a model for other regulatory agencies to adopt and use when formally establishing their own efficacy requirements; hence, the US focus in this article, but this information can be used in planning global trials with consultation of individual country regulations and guidance.

    Why are endpoints needed?

    Sound evidence of effectiveness is a crucial component of any regulatory agency’s benefit-risk assessment of a new product or use (i.e., a new indication). The need for an endpoint to measure the effectiveness of a drug stems from FDA’s need for substantial evidence, specifically called for in the 1962 Kefauver Harris Amendment and in 21 CFR 314.50 5.iii.v which requires that a marketing application contain, “data demonstrating substantial evidence of effectiveness for the claimed indications.” Substantial evidence was defined in section 505(d) of the FD&C Act as “evidence consisting of adequate and well-controlled investigations, including clinical investigations by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended or suggested in the labeling or proposed labeling hereof.”5

    An adequate and well controlled (A&WC) study is defined in 21 CFR 314.126.b as a trial containing (summarized):

  • clear statement of objectives
  • methods of analysis which are adequate to assess the effects of the drug
  • use of a valid study design
  • defined patient population
  • randomization of patients
  • minimization of bias
  • Valid or Accepted Endpoints: the methods of assessment of subjects' response are well-defined and reliable. The protocol for the study and the report of results should explain the variables measured, the methods of observation and criteria used to assess response.
  • Clinical Benefit

    FDA would like efficacy endpoints, if not already issued in a guidance document, to incorporate the mantra of “feels, functions or survive” which is collectively defined as clinical benefit. Clinical benefit is a clinically meaningful effect of an intervention, i.e., a positive effect on how an individual:

  • feels (e.g., symptom relief)
  • functions (e.g., improved mobility, improvement or delay in the progression of a disease or condition)
  • survives (e.g.,  time in delay to death in comparison to a natural history cohort)
  • Clinical benefit should be meaningful and understandable to prescribers and patients and can be measured directly or indirectly (indirect assessment needs justification for its value as a replacement for how patients survive, feel or function).6,7

    Clinical Benefit Endpoints that have supported drug approval have included important clinical outcomes (e.g., increased survival, symptomatic improvement), but also have included effects on established (validated) surrogate endpoints (e.g., blood pressure, serum cholesterol).8,9

    The caveat here is if there is no instrument to measure how a patient “feels” or “functions,” one’s company might need to develop and validate a patient reported outcome to capture and measure this.

    Table 1. Overview of the Possible Clinical Trial Endpoints. Term Definition Endpoint

    An endpoint is a primary or secondary outcome used to judge the effectiveness of a treatment; it is a precisely defined variable intended to reflect an outcome of interest that is statistically analyzed to address a particular research question. Synonyms include: outcome, variable, parameter or marker.

    An endpoint typically specifies the type of assessments made, the timing of those assessments, the assessment tools used and possibly other details, as applicable, such as how multiple assessments within an individual are to be combined.10

    An example of endpoints are survival, improvements in quality of life, relief of symptoms and disappearance of the tumor.11

    Well-defined and reliable (21CFR 314.126)

    Appropriate for the target population

    Appropriate for the target indication

    Adequate measurement properties, e.g., content validity: PRO development relies on patient input to support content validity12

    Using end points that have already been approved by the regulatory authority makes the most sense, but if a new endpoint is being used, then it is necessary to prove that this endpoint is a valid measure of drug success.

    Primary Endpoint Primary endpoints means the outcome or event that most accurately measures the benefit of the therapy/drug/intervention being studied (efficacy); this is the most clinically important endpoint. This is the main question the sponsor is most interested in answering and one that is capable of being answered (i.e., “Does the intervention alter mortality rates or change baseline blood pressure, the number of deaths, the difference in survival between the treatment group and the control group, disease progression or death). There is usually only one primary endpoint. Most of all the primary endpoint needs to be clinically meaningful and recognized by regulators as being clinically meaningful or confer clinical benefit (for new indications this can be a challenge) and should reflect the accepted norms and standards in the relevant field of research. There should be sufficient evidence that the primary variable can provide a valid and reliable measure of some clinically relevant and important treatment benefit in the patient population described by the inclusion and exclusion criteria.13-16 Secondary Endpoint

    Typically, secondary endpoints are related to toxicity and undesired effects of the new therapy (safety) or to demonstrate additional effects on the disease or condition. The secondary questions need to support and relate to the primary objective and it used to demonstrate additional effects. For the primary objective of “Does the intervention alter mortality rates?” The secondary objective could look for cause of cardiac death, when death occurred or other cardiac incidents, such as:

  • coronary heart disease mortality
  • incidence of nonfatal myocardial infarction
  • incidence of stroke
  • reduction is risk factor
  • Secondary endpoints also may provide evidence that a particular mechanism underlies a demonstrated clinical effect (e.g., a drug for osteoporosis with fractures as the primary endpoint, and improved bone density as a secondary endpoint).17

    Positive results on the secondary endpoints can be interpreted only if there is first a demonstration of a treatment effect on the primary endpoint.

    Exploratory Exploratory endpoints may include clinically important events that are expected to occur too infrequently to show a treatment effect or endpoints that for other reasons are thought to be less likely to show an effect but are included to explore new hypotheses.18 Intermediate Clinical Endpoint In a regulatory context, an endpoint measuring a clinical outcome that can be measured earlier than an effect on Irreversible Morbidity or Mortality (IMM) and that is considered reasonably likely to predict the medical product’s effect on IMM or other clinical benefit. The intermediate clinical endpoint may be a basis for full approval if the effect on the endpoint is considered clinically meaningful. It also may be a basis for accelerated approval if the IMM effect is considered critical for use of the drug or for expedited access for medical devices intended for unmet medical need for life threatening or irreversibly debilitating diseases or conditions. Multiple Primary Endpoints (Co-primary Endpoints)

    It may sometimes be desirable to use more than one primary variable, each of which (or a subset of which) could be sufficient to cover the range of effects of the therapies.19

    Multiple endpoints may be needed when determining that the drug confers a clinical benefit depends on more than one disease aspect or outcome being affected. Multiple endpoints may also be used when:

  • there are several important aspects of a disease or several ways to assess an important aspect
  • there is no consensus about which one will best serve the study purposes
  • an effect on any one will be sufficient as evidence of effectiveness to support approval
  • In some cases, multiple aspects of a disease may appropriately be combined into a single endpoint, but subsequent analysis of the components is generally important for an adequate understanding of the drug’s effect.20

    Multiple primary endpoints become co-primary endpoints when it is necessary to demonstrate an effect on each of the endpoints to conclude that a drug is effective.

    An example is treatment of migraine headaches; although pain is the most prominent feature, migraine headaches are also often characterized by the presence of photophobia, phonophobia, and nausea, all of which are clinically important.

    Composite Endpoints

    There are some disorders for which more than one clinical outcome in a clinical trial is important, and all outcomes are expected to be affected by the treatment.21

    Rather than using each as a separate primary endpoint (creating multiplicity) or selecting just one to be the primary endpoint and designating the others as secondary endpoints, it may be appropriate to combine those clinical outcomes into a single variable or “composite” endpoint,” using a predefined algorithm (e.g., the rating scales used in arthritis, psychiatric disorders, and elsewhere).  This method is different than multiple primary endpoints and useful to study drugs if component events are infrequent and each component is clinically meaningful.22

    Composite endpoints are often used when the goal of treatment is to prevent or delay morbid, clinically important but uncommon events (e.g., use of an anti-platelet drug in patients with coronary artery disease to prevent myocardial infarction, stroke and death).

    Surrogate Endpoints

    When direct assessment of the clinical benefit (or outcomes) to the subject through observing actual clinical efficacy is not practical, indirect criteria may be considered. A surrogate endpoint is a laboratory measure or a physical sign intended to be used as a substitute for a clinically meaningful endpoint and that is reasonably likely to predict clinical benefit (based on epidemiologic, therapeutic, pathophysiologic or other evidence per 21 CFR 314.510). Such surrogates are less well-established than surrogates in regular use, such as blood pressure for stroke, cholesterol for cardiovascular disease or HIV load for development of AIDS23 and new surrogates need to be validated. Relationships between clinical and surrogate variables for one product do not necessarily apply to a product with a different mode of action for treating the same disease.24,25

    From a US regulatory standpoint, surrogate endpoints and potential surrogate endpoints can be characterized by the following level of clinical validation:

  • validated surrogate endpoint
  • reasonably likely surrogate endpoint
  • candidate surrogate endpoint26
  • A list of novel drugs approved using surrogate endpoints can be found on Table of Surrogate Endpoints That Were the Basis of Drug Approval or Licensure

    Pitfalls of using surrogate endpoints include:

  • uncertainty about clinical benefit
  • potential lack of correlation with outcome variable
  • lack of standardization or validation through multiple studies
  • missing long term data
  • possibility of undiscovered risks
  • less information about the occurrence of rare or delayed adverse events27
  • The level of evidence necessary to determine whether a surrogate is validated or likely to predict clinical benefit is made on a case by case basis by FDA.28

    Reasonably Likely Surrogate Endpoint “An endpoint supported by strong mechanistic and/or epidemiologic rationale such that an effect on the surrogate endpoint is expected to be correlated with an endpoint intended to assess clinical benefit in clinical trials, but without sufficient clinical data to show that it is a validated surrogate endpoint. Such endpoints may be used for accelerated approval for drugs and potentially also for approval or clearance of medical devices. In the case of accelerated approval for drugs, postmarketing confirmatory trials have been required to verify and describe the anticipated effect on the irreversible morbidity or mortality or other clinical benefit.”29 Validated Surrogate Endpoint

    “An endpoint supported by a clear mechanistic rationale and clinical data providing strong evidence that an effect on the surrogate endpoint predicts a specific clinical benefit. A validated surrogate endpoint can be used to support marketing approval of a medical or tobacco product in a defined context without the need for additional studies to demonstrate the clinical benefit directly. Although the term has been used in a conceptually broader way, from a U. regulatory standpoint, a validated surrogate endpoint almost always refers to a biomarker.”30

    Validation information is available on the FDA website.

    Biomarkers

    “A defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes or responses to an exposure or intervention, including therapeutic interventions. Molecular, histologic, radiographic or physiologic characteristics are types of biomarkers. A biomarker is not an assessment of how an individual feels, functions, or survives. Categories of biomarkers include:”

  • susceptibility/risk biomarker
  • diagnostic biomarker (example: stage a disease)
  • monitoring biomarker (monitoring a response to therapy)
  • prognostic biomarker
  • predictive biomarker (predict a response to a drug)
  • pharmacodynamic/response biomarker
  • safety biomarker31
  • FDA’s Biomarker and Qualification Information

    Biomarkers Used as Outcomes List in Development of Approved Products (2007-2015)

    Drug Development Too Program and Initiatives

    What contribution is required from the RI strategist?

    Regulatory strategists or intelligence professionals are called upon to help support the clinical portion of the strategy document or development plan by laying out the regulatory acceptable endpoints over the course of development. This means the RI strategist will need to:

  • research guidance documents available to understand required endpoints
  • research global past precedent to understand what the regulatory agency has allowed as primary and secondary endpoints for approved drugs in the same class or indication (if no guidance exists)
  • If a company is studying a new indication, Key Opinion Leaders (KOL) will be needed to help form and lead a Scientific Advisory Board (SAB) to help ensure the company is using the most relevant and measurable endpoints.
  • Endpoints for novel indication will typically come from literature and vetted with the KOLs and eventually the regulatory agency.
  • bring KOLs to regulatory meetings; there are typically several meetings with a regulatory agency (and sometimes advisory committee meetings) to reach agreement on novel endpoints
  • research the literature to understand the Standard of Care (SOC) in the therapeutic area across geographical regions
  • understand the changes in the SOC landscape, i.e., forthcoming changes in treatment paradigms as reported by the KOLs (i.e., what the baseline treatment paradigm is and what upcoming treatments or diagnostics methods are being developed over the next few years that should be anticipated and brought into the “Strategy Playbook”)
  • understand the competitive landscape (i.e., what are the endpoints competitors are using, especially if novel or not the same as in the guidance document, if any)
  • plan regulatory interactions with regulatory authorities to propose, discuss and negotiate endpoints, especially if it is a first in class or a new indication (and again, this is an iterative process and novel endpoint agreement does not usually happen in a single meeting)
  • Some things like researching KOLs is obvious—you look at Pubmed or advocacy groups, but where do you start with the endpoints? And what exactly do you collect, where do you find it and what should the presentation back to the team look like?

    Evolution of Endpoints by Development Phase

    Research should be performed and information organized according to phases of development to ensure a reasonable comparison (Table 2).To be able to recommend what endpoints to use at what stage, it is important to understand the evolution of endpoints over the clinical development of a product; from a safety emphasis in early studies to an efficacy endpoint in later studies. Endpoints differ by indication and change as disease treatment does.

    Table 2. Endpoints by Phase Phase of Development Typical Endpoints Phase 1
  • Safety assessed after single and multiple dose administrations:
  • Adverse Events (AE)
  • Labs
  • Physical exam
  • Pharmacokinetics (PK)
  • Pharmacodynamic (PD) endpoints
  • Phase 2A
  • Safety assessed after single and multiple dose administrations:
  • Adverse Events (AE)
  • Labs
  • Physical exam
  • Pharmacokinetics (PK)
  • Dosing paradigm established
  • Exploratory efficacy endpoints used
  • Phase 2B
  • Safety assessments:
  • Adverse Events (AE)
  • Labs
  • Physical exam
  • Metrics used to establish efficacy further tested and refined, unless efficacy endpoints are dictated by a guidance document
  • Phase 3
  • Efficacy Endpoints refined in previous trials; divided into primary and secondary endpoints
  • Exploratory endpoints
  • Safety assessments:
  • Adverse Events (AE)
  • Labs
  • Physical exam
  • Endpoint Research Where to Start—Free and Fee Tools

    The first stop on any regulatory information gathering mission is to understand what tools are available (free versus fee tools), which ones are available to address a particular question and what each tool will provide for each piece of the puzzle. Table 3 provides a roadmap for endpoint exploration.

    Where to Start Endpoint Analysis Information Blocking

    Armed with the needed endpoint information and the tools to find it, the next step is to understand how to “block” the information so that it is usable for the analysis. There is a large morass of data to review and categorize, including literature, global guidance documents, past precedent (if available) and the endpoints of trials currently underway as these have typically been vetted (or at least discussed) with the agency for the study being conducted. Table 4 provides information to collect for each endpoint.

    Table 4. Endpoint Information Needed to Serve as a Basis for Analysis. Information Needed on Each Endpoint Where to Find it Why Regulatory Precedence and Acceptance

    Previous regulatory filings (Drugs@FDA (or similar))

    Clinicaltrials.gov listing

    Elsevier’s PharmaPendium

  • Understand if the proposed endpoints will be accepted or if you will need to work with regulators to gain their acceptance
  • Current Use of Endpoint in Research

    Country specific guidance documents

    Journal articles

    Drugs@FDA (or similar)

  • Understand what endpoints are being explored as primary, secondary and exploratory endpoints by researchers in the field as the scientific information could change during the development process
  • What does endpoint really measure?

    Journal articles

    Drugs@FDA (or similar)

  • Understand how to measure the indication.  Sometimes endpoints do not measure what you need them to and then you need to reevaluate the endpoint
  • Some endpoints measure what you want, some what you need for regulatory requirements and others what you need to understand what endpoints most appropriately measure activity in your indication
  • Positive and negative views on endpoint use

    Journal articles

    Drugs@FDA (or similar)

  • What are the pros and cons to using the proposed endpoints? 
  • Is the scientific information changing and will the endpoints be changing over the timeframe? 
  • Endpoint validated?

    Journal articles

    Drugs@FDA (or similar)

  • Is there a new indication that has a new endpoint? 
  • Is there a new way to measure an endpoint?
  • What are the endpoints that have been used to measure the indication in the literature by researchers?
  • What is the acceptance or perception of the endpoints by regulators?
  • What work will the sponsor need to conduct to validate the endpoint?
  • Does validation need to be done prior to use in a study or during the conduct of the study?
  • Will a patient reported outcome be needed or created?
  • Inclusion/Exclusion Population

    Journal articles

    Drugs@FDA (or similar)

    Elsevier’s PharmaPendium

    Country specific guidance documents

  • The indication and patient population is defined by the study’s inclusion and exclusion criteria; this needs to be defined carefully as it will affect the outcome of the development program
  • Only the endpoints that are used most frequently or have past regulatory precedence should have an in-depth analysis conducted; all other should be high level reporting until the team agrees more analysis is needed. Once the information is acquired to define the output, which can differ vastly depending on the free or fee tools used, start constructing the output.

    Endpoint Analysis Steps for Information Gathering and Initial Analysis Endpoint Analysis: Free
  • Go to drugs.com and find out what other drugs are in the same class and/or indication; utilize in house expertise as well to help refine the list
  • Add drug names to list in an excel spreadsheet
  • Cull endpoint information initially from the label—cannot find the label in drugs.com or Drugs@FDA? Go to the FDA Online Label Repository where labels are archived
  • Refine list, if in oncology, with the help of NIC databases (Cancer Drug Approval Endpoints, Efficacy Endpoints in Oncology Clinical Trials)
  • Research available global guidance documents in indication (Intelligence Tools, Links and Resources); cull endpoints recommendation into excel spreadsheet
  • Pull the Summary Basis of Approvals (Intelligence Tools, Links and Resources) in the countries of choice based on research
  • Pull out the endpoints used for all past precedent drug into an excel worksheet by phase of development
  • From the medical or administrative section (with meeting minutes), cull information on endpoints discussions and issues with it such as lack of validation
  • Research current clinical trials being conducted in a clinical trial registry for both the indication and class of drugs; add these to the growing spreadsheet (Table 5) (sometimes it helps to do this step first prior to all other activities):
  • Further refine the search by phase of development and download just the trials in Phase 1, Phase 2, etc., and review those items
  • Look at map of countries and the location of sites being used in the studies
  • Look at synonyms for the disease and review other trials possibly associated with the same disease, but called by a different name
  • Organize by drug name, stage of development and endpoints
  • Research the following literature on PubMed:
  • recent trials in the indication and endpoints used
  • SOC
  • Evolution in changes in the SOC
  • KOLs
  • Download/purchase literature for in-depth review
  • Utilize indication specific (if any) advocacy groups to help refine current endpoints being used by KOLs or to help provide a literature jumping off point; this can be done through an SAB or one on one meetings
  • Analyze the list of endpoints, what are the typical endpoints used, what are the least typical and do a deep dive into the endpoints used most often so there is greater clarity on them for team discussion.
  • Put in a format to present the findings to the development team, for group discussion (Table 5) and rate from most frequently used, least used and emerging endpoints
  • This list needs to be reviewed with the Strategy Team and further refined as the Playbook is developed (i.e., this process might need to be used a few times and vetted with experts and the regulators).
  • Table 5. Clinicaltrials.gov Output Into Excel.* Title Conditions Interventions Study Designs Outcome Measures Phases Enrollment and Study Type MLN0128 in Recurrent/Metastatic Merkel Cell Carcinoma Merkel Cell Carcinoma Drug: MLN0128

    Intervention Model: Single Group

    Assignment

    Masking: None (Open Label)

    Primary Purpose: Treatment

    Maximum Tolerated Dose (MTD)

    Overall Response Rate (ORR)

    Overall Survival (OS)

    Progression-Free Survival (PFS)

    Adverse Events (AEs)

    Response Biomarkers, including p4EBP1, PSK6, pCAD and Merkel cell polyomavirus (MCV)

    Large T antigen (LT) and small T antigen (ST)

    Phase 1

    Phase 2

    34

    Interventional

    F16IL2 Plus Paclitaxel in Metastatic Merkel Cell Carcinoma Merkel Cell Carcinoma

    Drug: Arm A: F16IL2 in combination with paclitaxel

    Drug: Arm B: Paclitaxel

    Allocation: Randomized

    Intervention Model: Parallel Assignment

    Masking: None (Open Label)

    Primary Purpose: Treatment

    Efficacy of F16IL2 in combination with paclitaxel vs. paclitaxel monotherapy (RECIST v1.1, irRC)

    Overall survival rate

    Treatment efficacy (ORR, DCR)

    Safety and tolerability of the combination treatment with F16IL2 and paclitaxel

    Phase 2

    90

    Interventional

    A Proof-of-Concept Trial of GLA-SE in Patients With Merkel Cell Carcinoma Merkel Cell Carcinoma Biological: GLA-SE

    Intervention Model: Single Group Assignment

    Masking: None (Open Label)

    Primary Purpose: Treatment

    Safety and feasibility

    Clinical efficacy and immunogenicity

    Phase 1

    10

    Interventional

    Adjuvant Therapy of Completely Resected Merkel Cell Carcinoma With Immune Checkpoint Blocking Antibodies Versus Observation Merkel Cell Carcinoma

    Drug: Ipilimumab

    Drug: Nivolumab

    Allocation: Randomized

    Intervention Model: Parallel Assignment

    Masking: None (Open Label)

    Primary Purpose: Treatment

    Disease-free survival (DFS) at 12 months

    Number of adverse events

    Overall survival rate at 12 months

    DFS rate at 12 months

    Phase 2

    177

    Interventional

    Study of the Drug Ipilimumab for Metastatic Merkel Cell Carcinoma Merkel Cell Carcinoma Drug: Ipilimumab

    Allocation: Non-Randomized

    Intervention Model: Single Group Assignment

    Masking: None (Open Label)

    Primary Purpose: Treatment

    Overall survival at 12 months with ipilimumab treatment

    Determine the best overall response rate, median survival, disease-specific survival and progression free survival

    Determine median survival, disease-specific survival and progression nfree survival

    Phase 2

    0

    Interventional

    QUILT-3.009: Study of aNK Infusions in Combination With ALT-803 in Patients With Stage III (IIIB) or Stage (IV) Merkel Cell Carcinoma (MCC)

    Stage IIIB Merkel Cell Carcinoma

    Stage IV Merkel Cell Carcinoma

    Biological: aNK (NK-92)

    Intervention Model: Single Group Assignment

    Masking: None (Open Label)

    Primary Purpose: Treatment

    Progression Free Survival

    Overall Response Rate

    Time to disease progression

    Overall survival

    Safety and tolerability of aNK in combination with ALT-803

    Quality of life assessment

    Phase 2

    24

    Interventional

    *Need to Specify Fields to Download. Endpoint Analysis: Fee Figure 1. Organized Endpoint Output for BizInt Smart Charts (Combined Output from a Variety of Clinical Registries). Brown-Tuttle-Fig-1.jpg
  • Go to PharmaPendium, input the indication and class as search terms, cull results for a list of drugs approved for indication and class and endpoints in medical reviews; utilize in house expertise to help refine the list; put results into an excel spreadsheet
  • Pull out the endpoints used for all past precedent drug into an excel worksheet, by phase of development
  • From the medical or administrative section (with meeting minutes) cull information on endpoints discussions and issues with it such as lack of validation
  • Research available global guidance documents in indication; cull endpoints recommendation into excel spreadsheet using Tarius or Clarivate Analytics Cortellis
  • Ask Nerac to conduct a literature search for you looking at SOC, KOLs, emerging treatments and endpoints used for indication
  • Or ask a Librarian to conduct the literature search for you
  • Ask librarian or literature search service to download/obtain literature
  • Review and put results into an excel spreadsheet
  • Analyze the list of endpoints, put in a format to present your findings to the development team, for group discussion
  • Regulatory Pathway Dictated by Type of Endpoint Used

    Something to keep in mind when finalizing and incorporating endpoints into a strategy, the type of endpoint selected can dictate the regulatory approval pathway that needs to be followed. Review Table 6 to ensure alignment with regulatory expectations.

    Table 6. Endpoints and Predicted Regulatory Pathway. Type of Endpoint What it Does Regulatory Pathway Clinical Benefit How a patient feels, functions or survives Regular* Validated Surrogate Recognized as validated through multiple definitive studies Regular* Surrogate Reasonably likely to predict clinical benefit Accelerated Approval *Could be accelerated or priority review based on the unmet medical need or seriousness of indication.32

    Communicating the Data Back to the Stakeholders

    Once the needed information is available to define the output, which can differ vastly depending on the free or fee tools used and the specific indication, begin constructing the output and understand what is needed for the output. One of the biggest issues in analyzing data, since it is so onerous, is the presentation back to the team and deciding the most efficient form is should take. On the backend, there is a lot of data that needs to be cleaned, merged or manually manipulated and since it is disparate, it can be very difficult to summarize, especially endpoints. Most teams want a high-level analysis that is interactive so as to answer immediate questions and an excel spreadsheet does not have visual appeal; this is where a “fee” product really is helpful in presenting a brightly colorful and interactive output.

    Case Study—Merkle Cell Carcinoma

    The following case study discusses the indication of the rare disease Merkle Cell Carcinoma (MCC) and demonstrates how to put the above information into practice. Note: only one drug has been approved for this indication [BAVENCIO [AVELUMAB]] (approved 23 March 2017).

    New Regulatory Intelligence Tool

    BizInt Smart Charts Drug Development Suite is purpose-built software designed to facilitate creating, customizing and distributing tabular reports from selected clinical trial, drug pipeline and biomedical journal databases. Reflecting more than 20 years of feedback from users in pharmaceutical and biotech companies, it replaces the need to write complicated macros and manually manipulate data in Excel and Word. Data from supported databases (see below) is imported and formatted into tables, and the fields/columns included in your report can be changed at any time. BizInt Smart Charts automatically identifies the same trial across different databases and the same drug across pipeline databases and has tools to merge different database records on the same trial into a single integrated row in your report.

    A second tool, VantagePoint - Smart Charts Edition, has the ability to further refine the data, extract terms and create visualizations for PowerPoint presentations. Table 7 provides an overview of the databases that BizInt Smart Charts can pull from to help compile endpoint information.

    Table 7. BizInt Smart Charts Drug Development Suite—Supported Databases. Supported Clinical Trial Databases Supported Pipeline Databases Supported Biomedical Journal Databases

    Registry:Clinical Trials.govEU Clinical Trials RegistryWHO ICTRP

    Commercial:Citeline TrialtroveAdis Clinical Trials InsightCortellis Clinical Trials

    Citeline PharmaprojectsClarivate Analytics CortellisIMS R&D FocusAdis R&D InsightClarivate Integrity

    Medline/PubMedBIOSISEMBASE

    BizInt Smart Charts was used to collect endpoint information from a variety of Clinical Trial Registries for MCC and this was compared with the collection and analysis times done without the tool (Table 8).  Overwhelmingly, the tool shaved more than 100 hours off of the task at hand (two weeks of work.)

    Table 8: Mining Clinical Trial Registry Data for Endpoints—Time Comparison of the Free and For Fee Tools Steps Taken Tools Used Free Time Fee Time Search databases for “Merkle Cell Carcinoma” and download results to excel spreadsheet

    WHO—ICTRP Search Portal

    Drugs@FDA Database

    10 min 10 min

    Open up the spreadsheets and combine the trials

  • Google Worksheets
  • MS Excel
  • 5 min

    (Figure 1)

    2 min

    Go through and remove the duplicates and/or merge the information for the same trials listed in multiple databases

  • Google Worksheets
  • MS Excel
  • 100+ min 5 min
  • Delete or move around fields so that pertinent information is displayed in first few rows
  • Hide rows so that they are still available but not distracting your analysis
  • Google Worksheets
  • MS Excel
  • 45+ min 20
  • Analyze what is pertinent to your program to be able to make recommendations to the team
  • Brain power and experience

    200+ min

    Brain power and experience

    200+ min
  • Put together the information in a way easily incorporated into the Strategy Playbook
  • Google Worksheets
  • MS Excel
  • 60+ min
  • PowerPoint
  • BizInt Smart Charts
  • 30 min
  • Put together information in a PowerPoint Slide for presentation to the team
  • Google Worksheets
  • MS Excel
  • PowerPoint
  • 60+ min
  • PowerPoint
  • BizInt Smart Charts
  • 30 min Total Time 480+ min ~297 min Case Study Conclusion

    Overall, while some of the steps are the same, the fee tools do provide quicker information output which can lead to quicker analysis and feedback to the team. BizInt Smart Charts and VantagePoint significantly cut down on the time it took to research endpoints making the time to respond to the team quicker and the output visually pleasing (which would have taken a lot longer to achieve manually) and interactive, which really worked well for the team and because questions were able to be answered on the spot versus looking through a pile of notes. 

    Summary

    As a parting note, remember the “Strategy Playbook” must be reviewed on an annual basis as scientific data and the requirements for a program change over time, so keeping complete notes and output are important to help evaluate data as it evolves.

    References
  • Multiple Endpoints in Clinical Trials. Guidance for Industry. January 2017. FDA website https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm536750.pdf. Accessed 21 September 2018.
  • Federal Food, Drug, and Cosmetic Act (FD&C). FDA website. https://www.fda.gov/RegulatoryInformation/LawsEnforcedbyFDA/FederalFoodDrugandCosmeticActFDCAct/default.htm. Accessed 21 September 2018.
  • Kefauver-Harris Amendments Revolutionized Drug Development. FDA website. https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm322856.htm. Accessed 21 September 2018.
  • Carpenter D. Reputation and Power. Organizational Image and Pharmaceutical Regulation at the FDA. Princeton University Press. https://press.princeton.edu/titles/9205.html. Accessed 21 September 2018.
  • Guidance for Industry. Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products. May 1998. FDA website. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072008.pdf. Accessed 21 September 2018.
  • BEST (Biomarkers, EndpointS, and other Tools) Resource. May 2018. FDA-NIH Biomarker Working Group. https://www.ncbi.nlm.nih.gov/books/NBK326791/pdf/Bookshelf_NBK326791.pdf. Accessed 21 September 2018.
  • Defining Clinical Benefit in Clinical Trials: FDA Perspective. Presentation by Jessica J. Lee, MD, MMSc. https://celiac.org/wp/wp-content/uploads/2015/04/great3-07.pdf. Accessed 21 September 2018.
  • Guidance for Industry. Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics. May 2007. FDA website. https://www.fda.gov/downloads/Drugs/Guidances/ucm071590.pdf. Accessed 21 September 2018.
  • FDA Facts: Biomarkers and Surrogate Endpoints. FDA website. https://www.fda.gov/aboutfda/innovation/ucm512503.htm. Accessed 21 September 2018.
  • Op cit 6.
  • National Cancer Institute (NCI) Dictionary of Cancer Terms. NCI website. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/endpoint. Accessed 22 September 2018.
  • Measuring How Patients Feel and Function. Presentation by Michelle Campbell, PhD. Roadmap to Engaging CDER Public Workshop. May 2017. FDA website. https://www.fda.gov/downloads/Drugs/NewsEvents/UCM558288.pdf. Accessed 22 September 2018.
  • Op cit 11.
  • HIV/AIDS Glossary. Clinical Endpoint. https://aidsinfo.nih.gov/understanding-hiv-aids/glossary/840/clinical-endpoint . Accessed 22 September 2018.
  • Op cit 1.
  • Guidance for Industry. E9 Statistical Principles for Clinical Trials. September 1998. FDA website.  https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm073137.pdf . Accessed 22 September 2018.
  • Op cit 1.
  • Op cit 1.
  • Op cit 16.
  • Op cit 1.
  • Op cit 1.
  • Op cit 16.
  • Op cit 9.
  • Op cit 16.
  • Clinical Trial Endpoints. Presentation by Eugene J. Sullivan, MD FCCP. FDA website. https://www.fda.gov/downloads/Training/ClinicalInvestigatorTrainingCourse/UCM337268.pdf. Accessed 23 September 2018.
  • Op cit 6.
  • FDA Regulatory Considerations for NASH Clinical Trial Endpoints. Presentation by Stephanie O. Omokaro, PhD. Global NASH Congress. https://www.slideshare.net/JaneWilliams25/fda-regulatory-considerations-for-nash-clinical-trial-endpoints
  • Sanyal AJ, Friedman SL, McCullough AJ  and Dimick-Santos L. “Challenges and Opportunities in Drug and Biomarker Development for Nonalcoholic Steatohepatitis.” Findings and recommendations from an American Association for the Study of Liver Diseases and FDA  Joint Workshop. https://www.ncbi.nlm.nih.gov/pubmed/25557690. Accessed 23September 2018.
  • Op cit 6.
  • Op cit 6.
  • Op cit 6.
  • Op cit 27.
  • About the Author

    Meredith Brown-Tuttle, RAC, FRAPS, is the principal consultant for Regulatorium, a company specializing in regulatory intelligence, writing and strategy. She is the author of IND Submissions: A Primer, published by Barnett, Regulatory Intelligence 101, published by RAPS, numerous articles and serves as chair of the RAPS Editorial Advisory Committee. She can be reached at theregulatorium@gmail.com.

    Cite as: Brown-Tuttle M. “The Regulatory Strategist Toolbox: Clinical Endpoint Analysis Tools.” Regulatory Focus. September 2018. Regulatory Affairs Professionals Society.



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    References :


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