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Posts Tagged ‘Clinical Trials’


Live Conference Coverage Medcity Converge 2018 Philadelphia: Clinical Trials and Mega Health Mergers

Reporter: Stephen J. Williams, PhD

1:30 – 2:15 PM Clinical Trials 2.0

The randomized, controlled clinical trial is the gold standard, but it may be time for a new model. How can patient networks and new technology be leveraged to boost clinical trial recruitment and manage clinical trials more efficiently?

Moderator: John Reites, Chief Product Officer, Thread @johnreites
Speakers:
Andrew Chapman M.D., Chief of Cancer Services , Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital
Michelle Longmire, M.D., Founder, Medable @LongmireMD
Sameek Roychowdhury MD, PhD, Medical Oncologist and Researcher, Ohio State University Comprehensive Cancer Center @OSUCCC_James

 

Michele: Medable is creating a digital surrogate biomarker for short term end result for cardiology clinical trials as well as creating a virtual site clinical trial design (independent of geography)

Sameek:  OSU is developing RNASeq tests for oncogenic fusions that are actionable

John: ability to use various technologies to conduct telehealth and tele-trials.  So why are we talking about Clinical Trials 2.0?

Andrew: We are not meeting many patients needs.  The provider also have a workload that prevents from the efficient running of a clinical trial.

Michele:  Personalized medicine: what is the framework how we conduct clinical trials in this new paradigm?

Sameek: How do we find those rare patients outside of a health network?  A fragmented health system is hurting patient recruitment efforts.

Wout: The Christmas Tree paradigm: collecting data points based on previous studies may lead to unnecessary criteria for patient recruitment

Sameek:  OSU has a cancer network (Orion) that has 95% success rate of recruitment.  Over Orion network sequencing performed at $10,000 per patient, cost reimbursed through network.  Network helps pharma companies find patients and patients to find drugs

Wout: reaching out to different stakeholders

John: what he sees in 2.0 is use of tech.  They took 12 clinic business but they integrated these sites and was able to benefit patient experience… this helped in recruitment into trials.  Now after a patient is recruited, how 2.0 model works?

Sameek:  since we work with pharma companies, what if we bring in patients from all over the US.  how do we continue to take care of them?

Andrew: utilizing a technology is critically important for tele-health to work and for tele-clinical trials to work

Michele:  the utilization of tele-health by patients is rather low.

Wout:  We are looking for insights into the data.  So we are concentrated on collecting the data and not decision trees.

John: What is a barrier to driving Clinical Trial 2.0?

Andrew: The complexity is a barrier to the patient.  Need to show the simplicity of this.  Need to match trials within a system.

Saleem: Data sharing incentives might not be there or the value not recognized by all players.  And it is hard to figure out how to share the data in the most efficient way.

Wout: Key issue when think locally and act globally but healthcare is the inverse of this as there are so many stakeholders but that adoption by all stakeholders take time

Michele: accessibility of healthcare data by patients is revolutionary.  The medical training in US does not train doctors in communicating a value of a trial

John: we are in a value-driven economy.  You have to give alot to get something in this economy. Final comments?

Saleem: we need fundamental research on the validity of clinical trials 2.0.

Wout:  Use tools to mine manually but don’t do everything manually, not underlying tasks

Andrew: Show value to patient

2:20-3:00 PM CONVERGEnce on Steroids: Why Comcast and Independence Blue Cross?

This year has seen a great deal of convergence in health care.  One of the most innovative collaborations announced was that of Cable and Media giant Comcast Corporation and health plan Independence Blue Cross.  This fireside chat will explore what the joint venture is all about, the backstory of how this unlikely partnership came to be, and what it might mean for our industry.

sponsored by Independence Blue Cross @IBX 

Moderator: Tom Olenzak, Managing Director Strategic Innovation Portfolio, Independence Blue Cross @IBX
Speakers:
Marc Siry, VP, Strategic Development, Comcast
Michael Vennera, SVP, Chief Information Officer, Independence Blue Cross

Comcast and Independence Blue Cross Blue Shield are teaming together to form an independent health firm to bring various players in healthcare onto a platform to give people a clear path to manage their healthcare.  Its not just about a payer and information system but an ecosystem within Philadelphia and over the nation.

Michael:  About 2015 at a health innovation conference they came together to produce a demo on how they envision the future of healthcare.

Marc: When we think of a customer we think of the household. So we thought about aggregating services to people in health.  How do people interact with their healthcare system?

What are the risks for bringing this vision to reality?

Michael: Key to experience is how to connect consumer to caregiver.

How do we aggregate the data, and present it in a way to consumer where it is actionable?

How do we help the patient to know where to go next?

Marc: Concept of ubiquity, not just the app, nor asking the provider to ask patient to download the app and use it but use our platform to expand it over all forms of media. They did a study with an insurer with metabolic syndrome and people’s viewing habits.  So when you can combine the expertise of IBX and the scale of a Comcast platform you can provide great amount of usable data.

Michael: Analytics will be a prime importance of the venture.

Tom:  We look at lots of companies that try to pitch technologies but they dont understand healthcare is a human problem not a tech problem.  What have you learned?

Marc: Adoption rate of new tech by doctors is very low as they are very busy.  Understanding the clinicians workflow is important and how to not disrupt their workflow was humbling for us.

Michael:  The speed at which big tech companies can integrate and innovate new technologies is very rapid, something we did not understand.  We want to get this off the ground locally but want to take this solution national and globally.

Marc:  We are not in competition with local startups but we are looking to work with them to build scale and operability so startups need to show how they can scale up.  This joint venture is designed to look at these ideas.  However this will take a while before we open up the ecosystem until we can see how they would add value. There are also challenges with small companies working with large organizations.

 

Please follow on Twitter using the following #hashtags and @pharma_BI

#MCConverge

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#innovation

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#healthcaremodels

#personalizedmedicine

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And at the following handles:

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https://pharmaceuticalintelligence.com/press-coverage/

 

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Blood Pressure Lowering

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Data analysis and publication of landmark NIH blood pressure study confirm that lower blood pressure target can reduce cardiovascular disease, deaths

http://www.nih.gov/news-events/news-releases/data-analysis-publication-landmark-nih-blood-pressure-study-confirm-lower-blood-pressure-target-can-reduce-cardiovascular-disease-deaths

 

NIH-supported researchers are reporting more details on a landmark study that announced preliminary findings in September showing a lower blood pressure target can save lives and reduce the risk of cardiovascular disease in a group of non-diabetic adults 50 years and older with high blood pressure. Results of the Systolic Blood Pressure Intervention Trial (SPRINT) appear in the current online issue of the New England Journal of Medicine and were discussed today at the American Heart Association 2015 Scientific Sessions in Orlando.

The study confirms that, in adults 50 years and older with high blood pressure, targeting a systolic blood pressure of less than 120 millimeters of mercury (mm Hg) reduced rates of cardiovascular events, such as heart attack and heart failure, as well as stroke, by 25 percent. Additionally, this target reduced the risk of death by 27 percent—as compared to a target systolic pressure of 140 mm Hg.

“SPRINT is part of a proud legacy of NIH-funded clinical trials that will change clinical practice and save lives for decades to come. These results reinforce the compelling public health importance of enhancing the awareness, treatment and control of hypertension in this country and around the world,” said Gary H. Gibbons, M.D., director of the National Heart, Lung, and Blood Institute (NHLBI), the primary sponsor of SPRINT.

The SPRINT study, which began in the fall of 2009, included more than 9,300 participants age 50 and older, recruited from about 100 medical centers and clinical practices throughout the United States and Puerto Rico. About 36 percent of participants were women, 58 percent were white, 30 percent were African-American, and 11 percent were Hispanic. The SPRINT study did not include patients with diabetes, prior stroke, or polycystic kidney disease, as other NIH trials were studying those particular populations. Approximately 28 percent were 75 or older and 28 percent had chronic kidney disease. The study tested a strategy of using blood pressure medications to achieve the targeted goals of less than 120 mm Hg (intensive treatment group) versus 140 mm Hg (standard treatment group). The NIH stopped the blood pressure intervention in August—a year earlier than planned—after it became apparent that this more intensive intervention was beneficial.

“When the benefits of the stronger intervention became apparent in SPRINT, we made a commitment to rapid public health communication and peer-reviewed publication of the study results,” Dr. Gibbons said. “We are pleased to present the details of the study’s potentially lifesaving findings at this time.”

In their report, investigators provided detailed data showing that both cardiovascular deaths and overall deaths were lower in the intensive treatment group.

Certain types of serious consequences were more common in the intensive group, including low blood pressure, fainting, electrolyte abnormalities, and acute kidney damage. However, other serious adverse events associated with lower blood pressure, such as slow heart rate and falls with injuries, did not increase in the intensive group. In patients with chronic kidney disease, there was no difference in the rate of serious decline in kidney function between the two blood pressure goal groups.

“The benefits of more intensive blood pressure lowering exceeded the potential for harm, regardless of gender or race/ethnicity,” said study co-author Paul Whelton, M.D., of Tulane University School of Public Health and Tropical Medicine in New Orleans, Louisiana. He is chair of the SPRINT Steering Committee.

In addition to its primary cardiovascular outcome, the study continues to examine kidney disease, cognitive function, and dementia among the SPRINT participants; however, these results are not yet available as additional information will be collected and analyzed over the next year.

“Although the study provides strong evidence that a lower blood pressure target saves lives, patients and their health care providers may want to wait to see how guideline groups incorporate this study and other scientific reports into any future hypertension guidelines. In the meantime, patients should talk to their health care providers to determine whether this lower goal is best for their individual care,” said study co-author Lawrence Fine, M.D., Chief, Clinical Applications and Prevention Branch at NHLBI.

“It’s also important to remember that healthy lifestyle changes can make a difference in controlling high blood pressure,” Dr. Fine added. He emphasized the importance of following a healthy diet, being physically active, maintaining a healthy weight, as well as learning to check your blood pressure.

In addition to primary sponsorship by the NHLBI, SPRINT is co-sponsored by the NIH’s National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Neurological Disorders and Stroke, and the National Institute on Aging.

Part of the National Institutes of Health, the National Heart, Lung, and Blood Institute (NHLBI) plans, conducts, and supports research related to the causes, prevention, diagnosis, and treatment of heart, blood vessel, lung, and blood diseases; and sleep disorders. The Institute also administers national health education campaigns on women and heart disease, healthy weight for children, and other topics. NHLBI press releases and other materials are available online at http://www.nhlbi.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

NIH…Turning Discovery Into Health®

Landmark NIH study shows intensive blood pressure management may save lives

Embargoed for Release:

September 11, 2015, 10:30 AM EDT

Lower blood pressure target greatly reduces cardiovascular complications and deaths in older adults

More intensive management of high blood pressure, below a commonly recommended blood pressure target, significantly reduces rates of cardiovascular disease, and lowers risk of death in a group of adults 50 years and older with high blood pressure. This is according to the initial results of a landmark clinical trial sponsored by the National Institutes of Health called the Systolic Blood Pressure Intervention Trial (SPRINT). The intervention in this trial, which carefully adjusts the amount or type of blood pressure medication to achieve a target systolicpressure of 120 millimeters of mercury (mm Hg), reduced rates of cardiovascular events, such as heart attack and heart failure, as well as stroke, by almost a third and the risk of death by almost a quarter, as compared to the target systolic pressure of 140 mm Hg.

“This study provides potentially lifesaving information that will be useful to health care providers as they consider the best treatment options for some of their patients, particularly those over the age of 50,” said Gary H. Gibbons, M.D., director of the National Heart, Lung, and Blood Institute (NHLBI), the primary sponsor of SPRINT. “We are delighted to have achieved this important milestone in the study in advance of the expected closure date for the SPRINT trial and look forward to quickly communicating the results to help inform patient care and the future development of evidence-based clinical guidelines.”

High blood pressure, or hypertension, is a leading risk factor for heart disease, stroke, kidney failure, and other health problems. An estimated 1 in 3 people in the United States has high blood pressure.

The SPRINT study evaluates the benefits of maintaining a new target for systolic blood pressure, the top number in a blood pressure reading, among a group of patients 50 years and older at increased risk for heart disease or who have kidney disease. A systolic pressure of 120 mm Hg, maintained by this more intensive blood pressure intervention, could ultimately help save lives among adults age 50 and older who have a combination of high blood pressure and at least one additional risk factor for heart disease, the investigators say.

The SPRINT study, which began in the fall of 2009, includes more than 9,300 participants age 50 and older, recruited from about 100 medical centers and clinical practices throughout the United States and Puerto Rico. It is the largest study of its kind to date to examine how maintaining systolic blood pressure at a lower than currently recommended level will impact cardiovascular and kidney diseases. NIH stopped the blood pressure intervention earlier than originally planned in order to quickly disseminate the significant preliminary results.

The study population was diverse and included women, racial/ethnic minorities, and the elderly.  The investigators point out that the SPRINT study did not include patients with diabetes, prior stroke, or polycystic kidney disease, as other research included those populations.

When SPRINT was designed, the well-established clinical guidelines recommended a systolic blood pressure of less than 140 mm Hg for healthy adults and 130 mm Hg for adults with kidney disease or diabetes. Investigators designed SPRINT to determine the potential benefits of achieving systolic blood pressure of less than 120 mm Hg for hypertensive adults 50 years and older who are at risk for developing heart disease or kidney disease.

Between 2010 and 2013, the SPRINT investigators randomly divided the study participants into two groups that differed according to targeted levels of blood pressure control. The standard group received blood pressure medications to achieve a target of less than 140 mm Hg. They received an average of two different blood pressure medications. The intensive treatment group received medications to achieve a target of less than 120 mm Hg and received an average of three medications.

“Our results provide important evidence that treating blood pressure to a lower goal in older or high-risk patients can be beneficial and yield better health results overall,” said Lawrence Fine, M.D., chief, Clinical Applications and Prevention Branch at NHLBI. “But patients should talk to their doctor to determine whether this lower goal is best for their individual care.”

The study is also examining kidney disease, cognitive function, and dementia among the patients; however, those results are still under analysis and are not yet available as additional information will be collected over the next year.  The primary results of the trial will be published within the next few months.

In addition to primary sponsorship by the NHLBI, SPRINT is co-sponsored by the NIH’s National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Neurological Disorders and Stroke, and the National Institute on Aging.

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Transparency in Clinical Trials

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Does Pharma Really Want Transparency In Clinical Trials?

Ed Miseta, Chief Editor, Clinical Leader
Follow Me On Twitter @outsourcedpharm
http://www.clinicalleader.com/doc/does-pharma-really-want-transparency-in-clinical-trials-0001

 

My recent article on transparency in clinical trials, featuring Dr. Brad Thompson, CEO of Oncolytics, solicited a good number of comments and emails from readers. While most readers agree that more transparency would be good for patients and the industry, there seems to be a lot of disagreement over how it can be achieved, and if it can actually be achieved at all.

To recap, Thompson believes we still have a long way to go, and questioned whether true transparency would ever be achieved. His primary argument noted researchers who want to be published will not put much focus on neutral or negative trials, and even the press releases put out by sponsors include a limited amount of information.

One reader that works for a CRO made the following comment: “Dr. Thompson from Oncolytics made some very interesting comments about investigators holding back information. An investigator will enter patient data into an EDC system that is then verified by monitors. And that is just one of a number of sites. These investigators will generally know when a drug is working and when it is not. As a CRO, I often saw statistical outputs on blinded studies where you could see where the data was trending. Even data guys can tell if a drug is working by the data results and improvements in patients.”

If physicians and researchers are able to see clear results even when the data is still in the process of being collected, then what is the problem with being more transparent? One possible explanation is that once physicians know a drug will not work, they will no longer continue to place patients at risk by having them participate in the trial. This could be done for purely ethical reasons.

But there may also be reluctance to greater transparency on the part of the pharma company. “No drug company truly wants transparency because it leaves the results and outcomes more open to interpretation, mainly by Kaiser, Blue Cross and other groups,” noted another reader.  “Pharma companies could cost themselves a lot of money in sales if they do not have the time to target and position.”

Investors Are A Consideration

There is still another consideration at play. If a study is not going well, would it be to the benefit of the executives of a company to share those results? Let’s play devil’s advocate for a moment and assume you are the CEO of a biotech company. You’re making $500,000 a year with good benefits. You have several investors who have dumped millions of dollars into your company and your product. The study is targeted for four years, but within the first year you see results that indicate your drug is not going to produce the intended results.

“In that scenario, how prone would you be to ending the trial, saving the investors their remaining money, and losing your job?” notes one reader. “Are companies prone or pressured to locate new targets for therapy or identifying reasons to extend the trials, sometimes for a few years or longer?”

All of us have heard discussions about the possibility of electronic medical records (EMRs) someday replacing electronic data capture (EDC). According to one email I received, this will never happen because of the physician issue mentioned above. After all, if patient results were posted in the EMR and every doctor on the network has access to the information, everyone would know if I drug was not having the desired effect. As soon as that happens, promises of riches being delivered to investors will fall by the wayside, and executives will be out of jobs.

“Within big pharma, this is called job preservation,” noted another reader. “If funding for the trial is cut, I am out of a job. At the same time, trial results are not getting any better for patients. Years ago about one in three trials resulted in a successful outcome. Then it went to one in four. Today that success rate is around 15 percent with R&D commitment at about 12% (down from approximately 28%). It appears that the industry is run by money and managed by guys who know how to play the system.  If patients are the primary concern, the industry would target physicians who have the right patients, get enrollment done faster, and quickly identify if the product works as advertised.”

Limit Procedures And Additional Fields

Going back to Thompson’s comments, the problem is not always investigators wanting to get published. One reader noted oftentimes it is the in-house pharma and biotech doctors as well as researchers in academia who are anxious to get their names into publications. “Unfortunately, these are often the same people who include numerous unnecessary procedures in protocols. They will also ask for additional data fields to be included in EDC systems after study launch, which can delay database activity for two months. The reason is they see a hint of something and decide they want to dig deeper, even if the activity has nothing to do with the study results and the overall goal of the trial.”

The obvious fix to this would be executive leadership and study teams standing up and challenging the reason for inclusion of the additional data fields, which cost the industry both time and money. A large number of procedures should be challenged as well, especially if they are not standard of care.

“If a researcher sees a hint of something that seems to be interesting but has nothing to do with the study, they should engage one of the thought leaders to conduct an IIR program to see if the hypothesis is valid,” notes the reader. “They can do this while keeping the clinical program on track to closure without delay, and still appease their interests.”

Clearly, there are no easy solutions. Many pharma companies are certainly making a concerted effort to put the patient first, and I believe those efforts are sincere. But there is no question they must also be focused on funding and trial results – the industry has gone from one focused on a patient to one driven by investors, and that trend is unfortunate. Physicians and researchers will always have their own goals and aspirations, and placing additional burdens upon them could have the unintended consequence of driving them away from trial participation – poor sponsor/CRO pay practices and poorly written/detailed protocols have already moved many physician practices away from clinical trial participation. Coming up with a solution will likely involve bringing together all stakeholders for a more in-depth discussion on the topic, which unfortunately I don’t see happening anytime soon.

 

Transparency In Clinical Trials: Will It Ever Be Achieved?
Ed Miseta, Chief Editor, Clinical Leader
Follow Me On Twitter @outsourcedpharm

A lot has been made recently about transparency in clinical trials. In the EU a new regulation is about to address the issue, and CISCRPrecently sent a petition letter to the FDA asking it to pass a similar regulation in this country. The petition, signed by hundreds of patients, hopes to make trials results more accessible to patients.

It’s also not hard to understand why a patient participating in a trial would want to know the results of the study, and whether or not they received the active drug or a placebo. But while changes might help companies with patient recruitment and retention issues, will true trial transparency ever be possible?

Dr. Brad Thompson, CEO of biotech firm Oncolytics, believes we still have a very long way to go, and that perhaps pharma companies are not the ones that should be blamed. “I think a lot of people, patients especially, believe that companies are the roadblock in keeping the results of clinical studies from becoming public,” he says. “But personally, I believe it is a much wider issue than that, especially when it comes to finding out the results of unsuccessful trials.”

For example, Thompson looks at clinical investigators. He notes many of these individuals would like for their academic careers to progress. For these folks, the reporting of trial results, especially those that are negative or neutral, does nothing to advance their goals. It is not a deliberate action to conceal information, but the lack of an incentive to do so can often result in delays, provided the results are reported at all.

“If you are conducting a trial at 50 or 60 locations, it doesn’t take too many of them not reporting information to significantly slow down the ability of a sponsor to report on what is going on with the study,” notes Thompson. “And the more time that goes by, the more people will lose interest in doing so. Add to that the fact that there are no journals or annual meetings that are focused on reporting negative results. This is due to space and time limitations. If there are 100 speaking opportunities at the ASCO show in June, those spots will be given to people reporting exciting new results in cancer therapies. There is no time for, nor interest in, anyone reporting on therapies that didn’t work.”

From the standpoint of a public sponsor company, they will typically report negative trial results, but that will generally be via a press release, where there is very little detail. It’s also unlikely that a patient participating in a trial will be on the company’s PR distribution list. As a result, there is an entire system set up with no positive incentives to go into more detail about trials that did not go as planned.  That in itself is unfortunate, since we often learn as much from things that don’t work as we do from things that do.

“In many ways, knowing what didn’t work, or what caused a safety problem, can be more important than knowing what did work and knowing there were no safety problems,” adds Thompson. “Knowing of negative results will allow you to improve your own trials and continue to work to try and find something that does work. I think this is a bigger issue than people realize and it is not something that will be easy to address.”

All Requirements Fall On Sponsors

Of course in this entire daisy-chain of events, there is only one party involved that has a legal obligation to disclose positive or negative information on the trial. That is the sponsor company, which by law is required to disclose information about the trial. Failure to report something could result in a criminal offense. If an investigator doesn’t disclose something, they do not face the same negative repercussions.

“If you talk to an attorney from any sponsor company, they will tell you how important it is to disclose, disclose, disclose,” says Thompson. “They fully understand the importance of doing that. The situation might be slightly different in privately-held companies, because public companies have an obligation to their investors. But even then they have a duty of disclosure under the investment terms. More often than not the investors are sitting on your board of directors and would be privy to the information anyway.”

On a positive note, Thompson is quick to note that most companies, investigators, and researchers he knows want to disclose as much as they possibly can.  There are just a number of soft reasons that might end up keeping them from getting into more detail than they do. For example, there is generally the same amount of content going into a press release regardless of whether or not the trial was successful. He notes no one on the planet is going to put out a 30-page press release covering the detail of a clinical study, whether it was good or bad.

For that reason, most of the press releases that go out are seldom more than two pages, with just a few sentences on the results and the safety aspects. While that will meet the disclosure standards, it certainly does not disclose much detail to the investigators or others who wish to know the details.

“When you look closely at this situation, what you see is a system that is almost accidentally set up to inhibit full disclosure,” states Thompson. “The industry might feel it is good to publish negative results, but where would we publish them? Who is going to pay for it? Who is going to read it? It’s a difficult issue. You can try to induce people to do things, but if an investigator has a failed study, his academic career will not be helped by spending the weeks it would take to write a paper to be published. Especially if they can spend that time writing a paper on a study that did work. There is not a conspiracy of silence. It is just natural for people to want to focus on things that will help them out with their careers.”

More Information Benefits Patients

There are other reasons for reporting as much information as possible. Patients appreciate the information, but from the sponsor perspective, more information might mean coming up with better versions of existing medicines. Thompson likes to use bone marrow studies as an example of how more information can be helpful to patients. When physicians first started using radiation to kill off bone marrow for certain types of leukemia patients, that marrow had to be replaced. It was discovered that bone marrow transferred from people who did not match the patient’s tissue type caused them to perform better…but only for a period of time. After that, the patients began to die quicker. Still, researches published the complete findings.

“They could have reported that non-matching bone marrow works really well for six months and left it at that,” says Thompson. “But they opted to include the downside of the study as well. That led physicians to decide it would be used for emergency use only until a better match could be found. That knowledge ended up making these transplants better for the patients and better for the industry. I think in that case we were lucky that there was a positive effect to report along with the negative. If there was only the negative effect, I don’t know that it would have ever been published.”

Is There A Fix?

I wish I could report that there is an easy fix to this transparency issue. Unfortunately, there is not. According to Thompson, there are not a couple of adjustments that can be made to correct the problem.  After all, you cannot force a researcher to publish an article on a failed study if they have more important needs to attend to. You can’t force a company to produce or publish a 30-page press release or, if they did, force anyone to read it. Unfortunately, that is a reality of the industry.

“We need to come up with a mechanism where the end result is of benefit to the industry, such as people having access to needed information and disseminating it without the process being burdensome,” notes Thompson. “I honestly don’t know how you do that.”

There are so many pieces to this problem…the sponsor companies, the FDA, the investigators, the research sites. It is difficult to fix a problem when the players involved in it are so varied. Still, if this is an issue that is too complicated to tackle with all players at once, perhaps the best approach would be to take it one step at a time. If we put sponsors, patients, and investigators in a room together, all would likely be clamoring for the same end result.

“We would not see pockets of stakeholders fighting this,” adds Thompson. “A solution to this transparency problem would make everyone better off. It’s frustrating because everyone knows this is an issue, and that we have to do better. People who are a lot smarter than I am have spent time on this and were not able to come up with an answer.  But the fact that this is a complicated issue doesn’t mean we should throw our hands in the air and give up. Eventually we will have to produce a solution.”

 

Taking The “Risk” Out Of Risk-Based Monitoring

http://www.clinicalleader.com/doc/taking-the-risk-out-of-risk-based-monitoring-0002

The clinical trial landscape is continually evolving and with it, efforts in the improvement of participant safety and data integrity. CROs are beginning to transition from on-site monitoring, with 100% point-to-point source data verification, toward a risk-based monitoring (RBM) approach that utilizes source data review and more centralized monitoring techniques better adapted for mitigating risk.

While RBM has gained considerable attention in recent years, reluctance still remains around the approach—from uncertainty arising from the use of “risk” employed in its name to sponsors being wary of potential implications on data quality and regulatory inspection outcomes.

Despite these concerns, there is a growing consensus that risk-based approaches to monitoring, focused on risks to the most critical data elements and processes necessary to achieve study objectives, are more likely than routine visits to all clinical sites and 100% source data verification to ensure subject protection, data integrity, and overall study quality.

 

Improve the Inclusion & Exclusion Criteria for Your Next Clinical Trial

http://www.clinicalleader.com/doc/improve-the-inclusion-exclusion-criteria-for-your-next-clinical-trial-0001

 

 

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Investigator Initiated Clinical Trials

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

The Art and Science of Investigator-Initiated Trials (IITs) 
IITs Can Be an Effective Way to Obtain Proof-Of-Concept Data More Quickly Than the Bureaucracy of a Large Firm Would Allow

Gerald L. Klein, M.D. Peter C. Johnson, M.D.      http://www.genengnews.com/insight-and-intelligence/the-art-and-science-of-investigator-initiated-trials-iits/77900560/

The investigator-initiated trial (IIT) is a unique type of clinical trial in which the clinician is both the sponsor and the investigator.

A clinical investigation is defined as an experiment in which a drug or device is administered or dispensed to, or used, involving one or more human subjects. Such an experiment is any use of a drug or device [whether approved or unapproved] except for the use of a marketed drug or device in the course of medical practice.

A sponsor of an investigational new drug (IND) application is the party who submits the application to FDA. In the absence of any other sponsor (e.g., pharmaceutical company), the investigator conducting the proposed clinical investigation is the sponsor of the IND application (when needed), as outlined here:

Investigator IND
21 CFR 312.3 and ICH E-6 (GCPs) 1.54
— Plans, designs, conducts, monitors, manages the data, prepares reports, and oversees all regulatory and ethical matters
— 21 CFR §312 Subpart D

This person takes on the regulatory responsibility of initiating and conducting a clinical trial. These trials may either be post-marketing studies or for unapproved products or indications.

IITs can be an effective tool for both large and small biopharmaceutical companies. If this program is conducted properly it may be a way to obtain expedited proof-of-concept data more quickly than the internal bureaucracy of a large company would allow. The IIT program should be conducted in a transparent, compliant, best practice manner to ensure proper execution of a quality program, which will subsequently allow the optimum use of the generated data.

 

 

 

 

 

Table 1 lists potential advantages of undertaking an IIT to both the company who owns the product and the investigator.
http://www.genengnews.com/Media/images/AnalysisAndInsight/thumb_Nov5_IITs_Table1_altered7722322014.jpg

From the company perspective, the IIT should be separated from marketing and kept under the auspices of medical affairs, in order to help comply with 68 Fed. Reg. 23736 (anti-kickback regulation). A formal set of standard procedures should be in place for these studies. A company may decide to use a committee consisting of representatives from medical affairs, clinical research, regulatory, and commercial, to determine which IITs should be approved and funded. It is desirable to provide instructions about the application process for IITs on a company’s website with the company’s required information needed to review and make a decision.

Medical Science Liaisons (MSLs). These are highly trained medical educators (typically but not always M.D.s or Ph.D.s) who convey the science rationale behind medical products to clinicians—and respond to their scientific queries. MSLs may not be involved in selling products and should not report to a commercial superior.

MSLs should play an important role in communicating the areas of research that your company is interested in pursuing to the appropriate key opinion leaders (KOLs). They should artfully explain the types of studies that the company would be willing to support financially, the types of trials for which they would provide only product support, and those trial types that they will not support at all. The MSLs should also discuss with KOLs what additional scientific support they could provide if needed. Examples of this include support for data management and statistical analysis.

Some important regional KOLs may not be very experienced in the design, conduct, and requirements of clinical trials and may need additional assistance from an MSL. The MSL should explain the necessary steps for applying to the company for an IIT grant. Rather than trying to teach an inexperienced clinician directly how to undertake an IIT, it may be more effective to unite him/her with a more experienced physician who has the same interest as the original KOL. Collaboratively, they can work on the IIT and more easily overcome potential obstacles.

When the IIT has been completed, the medical affairs team should discuss its interest in sponsoring the results that will be presented at an appropriate scientific conference, either in the form of a poster or an oral podium presentation. The investigator may need some assistance in editing and formatting the data for such a presentation as well as similar help in the preparation and submission of a manuscript. Some companies may want to pay for the article to be an open access publication, so that a larger audience may read the manuscript without having to pay a journal fee.

Types of Clinical Trials

There are diverse types of clinical trials that could provide significant scientific data and impact both product development and commercial operations. These include pharmacoeconomic, quality of life, observational studies, and both retrospective and prospective double- and single-blinded randomized, controlled trials.

Open-label studies such as case-control trials are not blinded, but can provide valuable scientific information at a lower cost than double-blind studies. Epidemiological studies can determine the specific risk factors in a population and then, using a prophylactic study design, determine with reasonable assurance the effectiveness of a therapeutic or device to prevent or decrease the problem. Patient reported outcomes (PROs) are becoming increasing important and widespread. In this type of trial the results come directly from the patient.

“Pragmatic” studies evaluate the real-life effectiveness of a product by the way the product is actually being used by healthcare providers, hospitals, and patients. They can be quite effective in comparing diverse treatments. A well-known example of this was a pragmatic study published in the New England Journal of Medicine comparing the use of a once per day tablet (leukotriene antagonist) versus an inhaled corticosteroid in the first study and a long acting bronchial dilator in the second study for treatment of bronchial asthma.

Most experts thought that because the inhalers had been shown to be so efficacious in randomized clinical trials that it would easily win in a comparative study. Yet the authors concluded that the results found no significant difference in the efficacy results. However, adherence was better in the use of a tablet than in the use of an inhaled steroid or long-acting bronchodilator.

In summary, a carefully planned and executed IIT strategy can provide quicker proof-of-concept data and accelerate drug and device development as well as provide increased marketing penetration of approved products.

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Hormonal Therapy, Complementary and Alternative Therapies – 9.4

Writer and Curator: Larry H. Bernstein, MD, FCAP

The following material has been covered from a different vantage point in previous writings. In the previous articles the focus was both antibacterial and anticancer resistance.  Much of the focus was on the metabolomic studies of substrate fluxes across cells and extracellular analyses to determine differences between cancer cell types in vitro.  This time I shall cover some of the selected ground with a different perspective.  Alternative medicines have been around for thousands of years. Much of it was based on readily available plants that had a pharmacological action.  This also gave rise to pharmaceuticals by extraction of the active compound. Such was the case with digitalis and also with Warfarin.

9.4.1 Use of complementary medicine by adult patients participating in cancer clinical trials

9.4.2 Complementary/Alternative Medicine Use in a Comprehensive Cancer Center and the Implications for Oncology

9.4.3 Trends in Alternative Medicine Use in the United States, 1990-1997 Results of a Follow-up National Survey

9.4.4 Courses Involving Complementary and Alternative Medicine at US Medical Schools

9.4.5 38% of Adults Use Alternative Medicine

9.4.6 Wheat germ extract (Avemar, Avé, AvéULTRA, AWGE, OncoMAR)

9.4.7 How Avemar Helps Fight Cancer

9.4.8  The anti-cancer action of curcumin (turmeric)

Introduction – PENDING

9.4.1 Use of complementary medicine by adult patients participating in cancer clinical trials
Sparber ABauer LCurt GEisenberg DLevin TParks SSteinberg SMWootton J
Oncology Nursing Forum [2000, 27(4):623-630]
http://europepmc.org/abstract/med/10833691

PURPOSE/OBJECTIVES: To document the prevalence, demographic correlates, patterns of use, and beliefs about complementary and alternative medicine (CAM) therapies of adult patients enrolled in National Cancer Institute (NCI) clinical trials. DESIGN: Prospective, cross-sectional, descriptive survey.
SETTING: W.G. Magnuson Clinical Center of the National Institutes of Health in Bethesda, MD. SAMPLE: Convenience sample of 100 English-speaking, adult patients with cancer admitted to intramural clinical trials.
METHODS: A standardized, 99-item questionnaire assessing use of CAM therapies pre- and postcancer diagnosis was administered by face-to-face interview. MAIN RESEARCH VARIABLES: Use of CAM therapies, beliefs, communication with physician. FINDINGS: 63% used at least one CAM therapy, with an average use of two therapies per patient. Men were significantly less likely to use a therapy than women; women were more likely to use numerous therapies. Cancer diagnosis seems to have had no influence overall on the frequency of use of CAM therapies. The major reasons stated for CAM use were for treatment-related medical conditions as well as depression, anxiety, and insomnia. The most frequently reported therapies were spiritual, relaxation, imagery, exercise, lifestyle diet (e.g., macrobiotic, vegetarian), and nutritional supplementation. Patients unanimously believed that these complementary therapies helped to improve their quality of life through more effective coping with stress, decreasing the discomforts of treatment and illness, and giving them a sense of control. CONCLUSIONS: Patients with cancer use various complementary therapies to cope with their disease and the rigors of clinical trials. Women and those with higher educational backgrounds were more frequent users.
IMPLICATIONS FOR NURSING PRACTICE: Nurses who provide care to subjects of biomedical research have an opportunity and responsibility regarding their patients’ use of CAM therapies. Nurses may use in-house resources to help evaluate subjects’ use of a CAM modality or to provide quality-of-life therapies such as relaxation, imagery, or healing touch. Discussing these health practices in a nonjudgmental manner adds to the assessment of patients’ coping skills and ability to make decisions about their health care.

9.4.2 Complementary/Alternative Medicine Use in a Comprehensive Cancer Center and the Implications for Oncology
MA Richardson, T Sanders, JL Palmer, A Greisinger, and SE Singletary
J Clin Oncol 18:2505-2514.
http://www.integratedhealthclinic.com/assets/byTopic/IntegrativeOncology/3-CAM%20Use%20in%20MD%20Anderson-J%20Clin%20Oncol%202000.pdf

Purpose: Oncologists are aware that their patients use complementary/ alternative medicine (CAM). As cancer incidence rates and survival time increase, use of CAM will likely increase. This study assessed the prevalence and predictors of CAM use in a comprehensive cancer center. Subjects and Methods: Subjects were English-speaking cancer patients at least 18 years of age, attending one of eight outpatient clinics at The University of Texas M.D. Anderson Cancer Center, Houston, TX, between December 1997 and June 1998. After giving written informed consent, participants completed a self-administered questionnaire. Differences between CAM users and nonusers were assessed by Chi square and univariate logistic regression analysis. A multivariate logistic regression model identified the simultaneous impact of demographic, clinical, and treatment variables on CAM use; P values were two-sided. Results: Of the 453 participants (response rate, 51.4%), 99.3% had heard of CAM. Of those, 83.3% had used at least one CAM approach. Use was greatest for spiritual practices (80.5%), vitamins and herbs (62.6%), and movement and physical therapies (59.2%) and predicted (P < .001) by sex (female), younger age, indigent pay status, and surgery. After excluding spiritual practices and psychotherapy, 95.8% of participants were aware of CAM and 68.7% of those had used CAM. Use was predicted (P < .0001) by sex (female), education, and chemotherapy. Conclusion: In most categories, CAM use was common among outpatients. Given the number of patients combining vitamins and herbs with conventional treatments, the oncology community must improve patient provider communication, offer reliable information to patients, and initiate research to determine possible drug-herb-vitamin interactions.

9.4.3 Trends in Alternative Medicine Use in the United States, 1990-1997 Results of a Follow-up National Survey
DM Eisenberg, RB Davis, SL Ettner, S Appel, S Wilkey, M Van Rompay; RC Kessler
JAMA. 1998; 280(18):1569-1575.
http://dx.doi.org:/10.1001/jama.280.18.1569

Context.  A prior national survey documented the high prevalence and costs of alternative medicine use in the United States in 1990. Objective. To document trends in alternative medicine use in the United States between 1990 and 1997. Design. Nationally representative random household telephone surveys using comparable key questions were conducted in 1991 and 1997 measuring utilization in 1990 and 1997, respectively. Participants. A total of 1539 adults in 1991 and 2055 in 1997. Main Outcomes Measures. Prevalence, estimated costs, and disclosure of alternative therapies to physicians.
Results. Use of at least 1 of 16 alternative therapies during the previous year increased from 33.8% in 1990 to 42.1% in 1997 (P≤.001). The therapies increasing the most included: herbal medicine, massage, megavitamins, self-help groups, folk remedies, energy healing, and homeopathy. The probability of users visiting an alternative medicine practitioner increased from 36.3% to 46.3% (P=.002). In both surveys alternative therapies were used most frequently for chronic conditions, including back problems, anxiety, depression, and headaches. There was no significant change in disclosure rates between the 2 survey years; 39.8% of alternative therapies were disclosed to physicians in 1990 vs 38.5% in 1997. The percentage of users paying entirely out-of-pocket for services provided by alternative medicine practitioners did not change significantly between 1990 (64.0%) and 1997 (58.3%) (P=.36). Extrapolations to the US population suggest a 47.3% increase in total visits to alternative medicine practitioners, from 427 million in 1990 to 629 million in 1997, thereby exceeding total visits to all US primary care physicians. An estimated 15 million adults in 1997 took prescription medications concurrently with herbal remedies and/or high-dose vitamins (18.4% of all prescription users). Estimated expenditures for alternative medicine professional services increased 45.2% between 1990 and 1997 and were conservatively estimated at $21.2 billion in 1997, with at least $12.2 billion paid out-of-pocket. This exceeds the 1997 out-of-pocket expenditures for all US hospitalizations. Total 1997 out-of-pocket expenditures relating to alternative therapies were conservatively estimated at $27.0 billion, which is comparable with the projected 1997 out-of-pocket expenditures for all US physician services. Conclusions. Alternative medicine use and expenditures increased substantially between 1990 and 1997, attributable primarily to an increase in the proportion of the population seeking alternative therapies, rather than increased visits per patient.

9.4.4 Courses Involving Complementary and Alternative Medicine at US Medical Schools
Miriam S. Wetzel, David M. Eisenberg, Ted J. Kaptchuk
JAMA. 1998; 280(9):784-787.
http://dx.doi.org:/10.1001/jama.280.9.784

Context. With the public’s increasing use of complementary and alternative medicine, medical schools must consider the challenge of educating physicians about these therapies. Objectives. To document the prevalence, scope, and diversity of medical school education in complementary and alternative therapy topics and to obtain information about the organizational and academic features of these courses. Design. Mail survey and follow-up letter and telephone survey conducted in 1997-1998. Participants. Academic or curriculum deans and faculty at each of the 125 US medical schools.
Main Outcome Measures. Courses taught at US medical schools and administrative and educational characteristics of these courses.
Results. Replies were received from 117 (94%) of the 125 US medical schools. Of schools that replied, 75 (64%) reported offering elective courses in complementary or alternative medicine or including these topics in required courses. Of the 123 courses reported, 84 (68%) were stand-alone electives, 38 (31%) were part of required courses, and one (1%) was part of an elective. Thirty-eight courses (31%) were offered by departments of family practice and 14 (11%) by departments of medicine or internal medicine. Educational formats included lectures, practitioner lecture and/or demonstration, and patient presentations. Common topics included chiropractic, acupuncture, homeopathy, herbal therapies, and mind-body techniques.
Conclusions. There is tremendous heterogeneity and diversity in content, format, and requirements among courses in complementary and alternative medicine at US medical schools.

9.4.5  38% of Adults Use Alternative Medicine
Rob Stein – Washington Post Staff Writer Dec 11, 2008
http://washingtonpost.com/wp-dyn/content/article/2008/12/10/AR2008121001601.html

More than one-third of adults and nearly 12 percent of children in the United States use alternatives to traditional medicine, according to a large federal survey released today that documents how entrenched acupuncture, herbal remedies and other once-exotic therapies have become.

The 2007 survey of more than 32,000 Americans, which for the first time included children, found that use of yoga, “probiotics,” fish oil and other “complementary and alternative” therapies held steady among adults since the last national survey five years earlier, and that such treatments have become part of health care for many youngsters.

“It’s clear that millions of Americans every year are turning to complementary and alternative medicine,” said Richard L. Nahin of the National Institutes of Health’s National Center for Complementary and Alternative Medicine, which released the survey. “The use of complementary and alternative medicine seems to have stabilized in the United States.”

The most commonly used are dietary supplements and herbal products such as echinacea, flaxseed oil and ginseng, followed by deep-breathing exercises, meditation, chiropractic therapy, massage and yoga. Although fewer Americans were using certain diets and trying herbal remedies such as echinacea to cure colds, the popularity of acupuncture, meditation, yoga and massage grew.
9.4.6 Wheat germ extract (Avemar, Avé, AvéULTRA, AWGE, OncoMAR)
http://mskcc.org/cancer-care/herb/wheat-germ-extract

Fermented wheat germ extract (WGE) was developed in the 1990s by Hungarian chemist Mate Hidvegi. It should not be confused with wheat germ oil. WGE is used as a dietary supplement by cancer patients in Hungary to improve quality of life (QoL).

Results from in vitro studies show that WGE has anticancer (1) (2) (3) (4) (5) (19), antimetastatic (6), and immunomodulatory (2) (7) effects. Although it appears to increase estrogen receptor (ER) activity, WGE enhanced efficacy of tamoxifen, an ER antagonist, in ER+ breast cancer cells (8) as well as cisplatin in ovarian cancer cell lines (5). Animal models suggest WGE can reduce cardiovascular symptoms due to chronic hypertension, diabetes, and obesity (9), mitigate symptoms associated with lupus (10), and that its antitumor effect is comparable to other endocrine treatments (11).

Data from pilot studies indicate a beneficial role for WGE in patients with colorectal cancer (12) and in reducing treatment-associated febrile neutropenia in pediatric cancer patients (13). It also prolonged survival of patients with melanoma when used with chemotherapy (14) (15). However, these effects must be confirmed by large-scale, well-designed clinical trials.

Because it potentiates estrogen receptor activity, patients with hormone-sensitive cancers should use WGE with caution.

What is Avemar?
http://avemar.info/what_is_avemar

Avemar is an all-natural, clinically proven, dietary supplement for cancer patients. Medical experts recognize Avemar as an effective supportive cancer treatment and recommend complementing the diet of concerned patients with Avemar.Scientific studies showed that Avemar also enhances the efficacy of conventional oncological treatments (surgery, radio-, chemo- and immunotherapy). With regular intake of Avemar, patients can relish a better quality of life and can enjoy a better lifestyle. Avemar is available in granulate and film-coated tablet form.

The active ingredient is Avemar pulvis, an all-natural compound made from fermented wheat germ extract using patented biotechnological processes. Since the invention of Avemar pulvis significant research has been undertaken – not only in the laboratory, but in test animals and human cancer patients as well. Numerous scientific studies have been conducted to study its safety profile and its effectiveness, including in vitroin vivo and human clinical research. Over 100 reports have been written for presentation or publication since 1998, and over 33 peer-reviewed scientific papers are currently accessible at PubMed database. All scientific publications are accessible at the official Avemar Research website.

9.4.7 How Avemar Helps Fight Cancer
Dr. David Williams
http://drdavidwilliams.com/avemar-cancer

Avemar is a naturally fermented wheat germ extract that has been subjected to a great deal of research scrutiny, particularly in the area of cancer treatment. What makes Avemar stand out among other known therapies is the fact that its effectiveness isn’t limited to any one specific type of cancer. So far it has exhibited positive effects against all forms of cancer cell lines tested.

Whether cancer cells proceed to replicate, grow, and eventually spread throughout the body is determined by enzymatic activity and their accessibility to various nutrients.

Pharmaceutical companies have focused their efforts to find cures for various forms of cancer. One of their top priorities (and one area with the greatest potential) has always been to uncover compounds that inhibit glucose metabolism in tumor cells.

Every form of cancer cell utilizes glucose at rates 10 to 50 times higher than that of normal healthy cells (a well-known phenomenon referred to as “the Warburg effect”). Unlike normal, healthy cells that utilize glucose primarily for energy, tumor cells use glucose to replicate cells. They convert glucose to nucleic acids (necessary for the formation of additional RNA) by a hexose monophosphate pathway. They also have to break down tissue in order to make proteins (needed for the cancer to continue to grow). This is termed cachexia.  In this sense the behavior of cancer proliferation is like a systemic infection.

In simple terms, cancer cells have only one function: proliferation. To achieve this function, cancer cells need large amounts of glucose that they can convert into building materials for new cells. As the tumor grows, more and more glucose is consumed.

Research indicates that Avemar works through several different mechanisms. One of its most unique benefits, however, is its ability to inhibit glucose metabolism in cancer cells.

Research at UCLA has demonstrated that Avemar reduces glucose flow into cancer cells—which inhibits their ability to produce additional nucleic acids and subsequently reduces their proliferation or growth. In the presence of Avemar compounds, cancer cells begin to utilize the available glucose to produce substances that actually inhibit cell division and stimulate programmed cell death (apoptosis) within the tumor.

As one report explains, decreased glucose consumption of the tumors results in a harmonizing of the patient’s metabolism—as well as weight gain, even in people with advanced cancers. As a result, patients treated with Avemar also have improved tolerance for surgery, radiation, and chemotherapy. Further, Avemar achieves these results without creating any toxicity or damage to normal, healthy cells. (Ann N Y Acad Sci. 07;1110:348–61)

This particular feature of Avemar explains why cancer patients using the product routinely experience an improved quality of life. They have less fatigue, pain, and depression, and experience an increase in appetite that can help them regain lost weight. (Medicus Anonymus/Pulmono 03;11 (Suppl 1):13–14) (24th Congress of the Hungarian Cancer Society, Budapest, Hungary 2001)

9.4.8  The anti-cancer action of curcumin (turmeric)
http://canceractive.com/cancer-active-page-link.aspx?n=1571

* Importantly, the spice can stop the action of the enzyme COX-2 known to produce negative, inflammation causing localised enzymes (eicosanoids). Such inflammation is a known precursor to cancer.

* It has also been shown to inhibit vascular epithelial growth factors. Every tumor needs a blood supply – the growth factors build one, but curcumin seems to stop them.

* It has been shown to ´re-awaken´ a key tumor suppressor gene.

* It has been shown to inhibit metastases.

* It has been shown to kill cancer cells (B lymphoma cells).

* It prevents regrowth of cancer stem cells which lie at the heart of many tumors

In the journal ´Genes and Nutrition´ (2011; 6(2):93-108) the whole issue of ´Epigenetics´ was exposed. It used to be thought that your genes controlled all and a problem in a gene meant you were in some way ´doomed´. This theory has been disproven and replaced by one that shows genes are just your blueprint; these blueprints are controlled, activated or suppressed by the localized environment. So hormones can affect their action, as can natural compounds in food. And curcumin seems to affect gene expression significantly. Such ´signaling pathways´ have been shown to be affected by curcumin.

An example of this ´signaling pathway´ modification came in research from the Ludwig-Maximilians University in Munich, Germany in 2012 which showed that curcumin can inhibit the formation of metastases in both prostate and breast cancer.  Both cancers spread throughout the body through the release of chemical messengers, pro-inflammatory cytokines CXCL1 and CXCL2, but curcumin alters the expression of these two damaging proteins.

Next, Cheryl Myers (head of Scientific Affairs and Education for EuroPharma Inc.) refers to curcumin as ´the anti-cancer herb´ because of its success in stopping cancer formation, replication and spread. Research also shows that curcumin increases the activity of certain anti-cancer drugs while protecting healthy cells and organs. It has been proven to reduce systemic inflammation and oxidative stress.

And researchers from the Dept. of Natural Science at Middlesex University have shown that curcumin and chokeberry can work together to induce cancer cell death (apoptosis) and stop the spread of malignant cancer cells. Their report (in Oncology Reports) was for brain tumors.

Dr Young S. Kim leading a team at the National Cancer Institute in America showed that curcumin was one of the natural compounds that could prevent cancer stem cells from re-growing and re-forming the cancer. Her conclusion even suggested patients could supplement!

The University of Missouri has shown curcumin can counter the dangerous effects of HRT and its link to breast cancer cause.  “The results of the study show that women could potentially take curcumin to protect themselves from developing progestin-accelerated tumors,” said the lead researcher. Synthetic progestin increases VEGF a protein that helps form blood supplies to developing tumors. Curcumin inhibits VEGF and thus reduces the potential of breast cancer to grow.

Professor Bharat Aggarwal Ph. D. in MD Anderson Department of Therapeutics has conducted a number of studies, for example showing that in a Phase II clinical trial, pancreatic cancer patients having no chemotherapy, it reduced tumor size. He believes it is effective against many types of cancer because it suppresses angiogenesis (the growth of blood vessels essential to a tumor). “The reason curcumin is so effective against cancer is that it hits not just a single target or cell signaling pathway but dozens of targets implicated in cancer.” It has also been shown to have a strong synergistic effect against cancer with resveratrol, and also with EGCG in green tea.

What is exciting the experts in cancer centers in America is that it can play a role against several of the steps in what is a multi-step cancer process. As such it would seem stupid to ignore it as a part of an Integrative or holistic cancer treatment program.

What are curcumin and turmeric?

Curcumin is the active ingredient of the Indian/Asian curry spice Turmeric.  To put this technically, curcumin is the principal curcuminoid in turmeric.  Curcuminoids are polyphenols.  Turmeric powder is ground from the root of a plant called Curcuma Longa, which is a member of the ginger family and is found throughout Southern Asia, even growing wild in the Himalayas.

This vivid yellow to brown spice was used, like many Asian spices and chillies, to hide the taste of stronger tasting meats and fish even those that might have gone a little off in such hot climates.  Like many such spices, it also performed a necessary and functional role it was a cleanser, a bacteria-killer in the stomach, protecting against tainted foods!

Curcumin/turmeric has been used in Ayurvedic medicine for thousands of years as a cleanser of the body.  It appears to work at a number of levels:

  1. It can inhibit unwanted bacterial action in the stomach and intestine:

For example (i) , University of Chicago researchers have shown it inhibits Helicobacter pylori, a bacterium known to be responsible for stomach ulcers and some stomach cancers.  In Ayurvedic medicine, curcumin was used in poultices for this same reason to kill unwanted bacteria.

  1. It is a significant anti-inflammatory:

Arachidonic acid is a precursor/stimulator of the production of bad eicosancids (see our reviews of omega 3 and vitamin D) and thus to inflammation, which is itself a precursor to certain cancers.  Curcumin has been found to inhibit several of the pre-inflammatory enzymes (e.g. COX2 and iNOS) in vitro and in vivo with animals.  Japanese research suggests it works in much the same way as salicylin.

  1. It boosts crucial cellular glutathione levels:

Glutathione is a crucial intracellular antioxidant, helping the cell maintain its correct oxygen levels and fight off the effects of stress hormones.  Research has shown that curcumin can prevent the action of an enzyme that limits glutathione production.

  1. It is a powerful antioxidant:

Turmeric extract tested more potent than garlic, omega 3 and cat´s claw (devil´s claw) said German research.

  1. It can help prevent liver damage

2010 research from St Louis has shown that it can turn off a protein called Leptin, which causes liver damage. It has also been shown to be capable of detoxifying the liver. Thus curcumin may be of help in keeping the liver healthy during chemotherapy cancer treatments.

  1. It can prevent and even ´treat´ cancer:

As we have covered above, curcumin can suppress tumor initiation, promotion and metastasis.  Extensive research over the last 50 years has indicated it can prevent and treat cancer. The anti-cancer potential stems from its ability to control gene signaling, and affect a wide variety of tumor cells, down-regulate transcription factors, down-regulate enzymes such as COX-2 and other inflammatories, cytokines, chemokines, cell-surface adhesion molecules, down-regulate growth factors, etc., etc.

Tufts have conducted research with breast cancer patients concluding that curcumin and isoflavanoids seem to inhibit the action of environmental estrogens.

UCLA have researched its potential with colorectal cancer (San Diego, Chauhen). And there are Clinical Trials underway (according to the Mayo Clinic to investigate curcumin as a way to prevent cancer in people with precancerous conditions, as a cancer treatment, and as a remedy for signs and symptoms caused by cancer treatments.

Much of the work original used cell cultures.  Increasingly studies use a variety of animals, and there have been human trials, even clinical trials, primarily with cervical cancer lesions and with gastrointestinal cancers.  So, although the biochemical knowledge is vast, the use of oral curcumin to prevent and treat cancer is still in its infancy.

Next, there is a problem maintaining effectiveness inside the cells; there are several studies that show oral consumption needs to be maintained in order to maintain blood and cellular levels.  But it is not as simple as curry every day!

Curcumin supplements may be heavily contaminated with everything from pesticides to other spices so you must choose a reliable supplier, ideally of curcuma longa. If you are thinking of buying Curcuma Longa you might like to look at the Natural Selection as they are based in the UK and they tend to have natural compounds that avoid pesticides. Click here. Alternatively in the USA you might like to go to the Natural News or Dr Mercola websites.

Counter indications

Some supplements contain piperine, supposedly to increase bio-availability.  This can interfere with certain drugs.

Curcumin can inhibit coagulation in vitro and so may be inadvisable if you are taking anti-coagulants.  It might increase the risk of bleeding.

It might also be advisable not to take it if you are pregnant or lactating.

In summary

Clearly there is a huge enthusiasm, even expectation, overseas for curcumin, if not in British hospitals and oncology departments.  But the real issue is can you take enough of it orally to deliver it in adequate doses to your breast or prostate cells?  Certainly curcumin (curcuma longa) was seen to be an important herb in the natural and successful treatment of prostate cancer that we covered in Cancer Watch (icon 2006, issue 3 ).  We will just have to wait and see whether this longstanding Ayurvedic medicine will curry favour with the UK medical fraternity.

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Notes from Opening Plenary Session – The Genome and Beyond from the 2015 AACR Meeting in Philadelphia PA; Sunday April 19, 2015

 

Reporter: Stephen J. Williams, Ph.D.

The following contain notes from the Sunday April 19, 2015 AACR Meeting (Pennsylvania Convention Center, Philadelphia PA) 9:30 AM Opening Plenary Session

The Genome and Beyond

Session Chairperson: Lewis C. Cantley, Ph.D.

Speakers: Michael R. Stratton, Tyler Jacks, Stephen B. Baylin, Robert D. Schreiber, Williams R. Sellers

  1. A) Insights From Cancer Genomes: Michael R. Stratton, Ph.D.; Director of the Wellcome Trust Sanger Institute
  • How do we correlate mutations with causative factors of carcinogenesis and exposure?
  • Cancer was thought as a disease of somatic mutations
  • UV skin exposure – see C>T transversion in TP53 while tobacco exposure and lung cancer see more C>A transversion; Is it possible to determine EXPOSURE SIGNATURES?
  • Use a method called non negative matrix factorization (like face pattern recognition but a mutation pattern recognition)
  • Performed sequence analysis producing 12,000 mutation catalogs with 8,000 somatic mutation signatures
  • Found more mutations than expected; some mutation signatures found in all cancers, while some signatures in half of cancers, and some signatures not found in cancer
  • For example found 3 mutation signatures in ovarian cancer but 13 for breast cancers (80,000 mutations); his signatures are actually spectrums of mutations
  • kataegis: defined as localized hypermutation; an example is a signature he found related to AID/APOBEC family (involved in IgG variability); kataegis is more prone in hematologic cancers than solid cancers
  • recurrent tumors show a difference in mutation signatures than primary tumor before drug treatment

 

  1. B) Engineering Cancer Genomes: Tyler Jacks, Ph.D.; Director, Koch Institute for Integrative Cancer Research
  • Cancer GEM’s (genetically engineered mouse models of cancer) had moved from transgenics to defined oncogenes
  • Observation that p53 -/- mice develop spontaneous tumors (lymphomas)
  • then GEMs moved to Cre/Lox systems to generate mice with deletions however these tumor models require lots of animals, much time to create, expensive to keep;
  • figured can use CRSPR/Cas9 as rapid, inexpensive way to generate engineered mice and tumor models
  • he used CRSPR/Cas9 vectors targeting PTEN to introduce PTEN mutations in-vivo to hepatocytes; when they also introduced p53 mutations produced hemangiosarcomas; took ONLY THREE months to produce detectable tumors
  • also produced liver tumors by using CRSPR/Cas9 to introduce gain of function mutation in β-catenin

 

See an article describing this study by MIT News “A New Way To Model Cancer: New gene-editing technique allows scientists to more rapidly study the role of mutations in tumor development.”

The original research article can be found in the August 6, 2014 issue of Nature[1]

And see also on the Jacks Lab site under Research

  1. C) Above the Genome; The Epigenome and its Biology: Stephen B. Baylin
  • Baylin feels epigenetic therapy could be used for cancer cell reprogramming
  • Interplay between Histone (Movers) and epigenetic marks (Writers, Readers) important for developing epigenetic therapy
  • Difference between stem cells and cancer: cancer keeps multiple methylation marks whereas stem cells either keep one on or turn off marks in lineage
  • Corepressor drugs are a new exciting class in chemotherapeutic development
  • (Histone Demythylase {LSD1} inhibitors in clinical trials)
  • Bromodomain (Brd4) enhancers in clinical trials
  1. D) Using Genomes to Personalize Immunotherapy: Robert D. Schreiber, Ph.D.,
  • The three “E’s” of cancer immunoediting: Elimination, Equilibrium, and Escape
  • First evidence for immunoediting came from mice that were immunocompetent resistant to 3 methylcholanthrene (3mca)-induced tumorigenesis but RAG2 -/- form 3mca-induced tumors
  • RAG2-/- unedited (retain immunogenicity); tumors rejected by wild type mice
  • Edited tumors (aren’t immunogenic) led to tolerization of tumors
  • Can use genomic studies to identify mutant proteins which could be cancer specific immunoepitopes
  • MHC (major histocompatibility complex) tetramers: can develop vaccines against epitope and personalize therapy but only good as checkpoint block (anti-PD1 and anti CTLA4) but personalized vaccines can increase therapeutic window so don’t need to start PD1 therapy right away
  • For more details see references Schreiker 2011 Science and Shankaran 2001 in Nature
  1. E) Report on the Melanoma Keynote 006 Trial comparing pembrolizumab and ipilimumab (PD1 inhibitors)

Results of this trial were published the morning of the meeting in the New England Journal of Medicine and can be found here.

A few notes:

From the paper: The anti–PD-1 antibody pembrolizumab prolonged progression-free survival and overall survival and had less high-grade toxicity than did ipilimumab in patients with advanced melanoma. (Funded by Merck Sharp & Dohme; KEYNOTE-006 ClinicalTrials.gov number, NCT01866319.)

And from Twitter:

Robert Cade, PharmD @VTOncologyPharm

KEYNOTE-006 was presented at this week’s #AACR15 conference. Pembrolizumab blew away ipilimumab as 1st-line therapy for metastatic melanoma.

2:02 PM – 21 Apr 2015

Jeb Keiper @JebKeiper

KEYNOTE-006 at #AACR15 has pembro HR 0.63 in OS over ipi. Issue is ipi is dosed only 4 times over 2 years (per label) vs Q2W for pembro. Hmm

11:55 AM – 19 Apr 2015

OncLive.com @OncLive

Dr Antoni Ribas presenting data from KEYNOTE-006 at #AACR15 – Read more about the findings, at http://ow.ly/LMG6T 

11:25 AM – 19 Apr 2015

Joe @GantosJ

$MRK on 03/24 KEYNOTE-006 vs Yervoy Ph3 stopped early for meeting goals of PFS, OS & full data @ #AACR15 now back to weekend & family

9:05 AM – 19 Apr 2015

Kristen Slangerup @medwritekristen

Keytruda OS benefit over Yervoy in frontline #melanoma $MRK stops Ph3 early & data to come @ #AACR15 #immunotherapy http://yhoo.it/1EYwwq8 

2:40 PM – 26 Mar 2015

Yahoo Finance @YahooFinance

Merck’s Pivotal KEYNOTE-006 Study in First-Line Treatment for…

Merck , known as MSD outside the United States and Canada, today announced that the randomized, pivotal Phase 3 study investigating KEYTRUDA® compared to ipilimumab in the first-line treatment of…

View on web

 

Stephen J Williams @StephenJWillia2

Progression free survival better for pembrolzumab over ipilimumab by 2.5 months #AACR15 @Pharma_BI #Cancer #Immunotherapy

11:56 AM – 19 Apr 2015

 

Stephen J Williams @StephenJWillia2

Melanoma Keynote 006 trial PD1 inhibitor #Immunotherapy 80% responders after 1 year @Pharma_BI #AACR15

 

References

  1. Xue W, Chen S, Yin H, Tammela T, Papagiannakopoulos T, Joshi NS, Cai W, Yang G, Bronson R, Crowley DG et al: CRISPR-mediated direct mutation of cancer genes in the mouse liver. Nature 2014, 514(7522):380-384.

 

Other related articles on Cancer Genomics and Social Media Coverage were published in this Open Access Online Scientific Journal, include the following:

Cancer Biology and Genomics for Disease Diagnosis

Introduction – The Evolution of Cancer Therapy and Cancer Research: How We Got Here?

Methodology for Conference Coverage using Social Media: 2014 MassBio Annual Meeting 4/3 – 4/4 2014, Royal Sonesta Hotel, Cambridge, MA

List of Breakthroughs in Cancer Research and Oncology Drug Development by Awardees of The Israel Cancer Research Fund

2013 American Cancer Research Association Award for Outstanding Achievement in Chemistry in Cancer Research: Professor Alexander Levitzki

Genomics and Epigenetics: Genetic Errors and Methodologies – Cancer and Other Diseases

Cancer Genomics – Leading the Way by Cancer Genomics Program at UC Santa Cruz

Genomics and Metabolomics Advances in Cancer

Pancreatic Cancer: Genetics, Genomics and Immunotherapy

Multiple Lung Cancer Genomic Projects Suggest New Targets, Research Directions for Non-Small Cell Lung Cancer

 

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Imaging-guided cancer treatment


Imaging-guided cancer treatment

Writer & reporter: Dror Nir, PhD

It is estimated that the medical imaging market will exceed $30 billion in 2014 (FierceMedicalImaging). To put this amount in perspective; the global pharmaceutical market size for the same year is expected to be ~$1 trillion (IMS) while the global health care spending as a percentage of Gross Domestic Product (GDP) will average 10.5% globally in 2014 (Deloitte); it will reach ~$3 trillion in the USA.

Recent technology-advances, mainly miniaturization and improvement in electronic-processing components is driving increased introduction of innovative medical-imaging devices into critical nodes of major-diseases’ management pathways. Consequently, in contrast to it’s very small contribution to global health costs, medical imaging bears outstanding potential to reduce the future growth in spending on major segments in this market mainly: Drugs development and regulation (e.g. companion diagnostics and imaging surrogate markers); Disease management (e.g. non-invasive diagnosis, guided treatment and non-invasive follow-ups); and Monitoring aging-population (e.g. Imaging-based domestic sensors).

In; The Role of Medical Imaging in Personalized Medicine I discussed in length the role medical imaging assumes in drugs development.  Integrating imaging into drug development processes, specifically at the early stages of drug discovery, as well as for monitoring drug delivery and the response of targeted processes to the therapy is a growing trend. A nice (and short) review highlighting the processes, opportunities, and challenges of medical imaging in new drug development is: Medical imaging in new drug clinical development.

The following is dedicated to the role of imaging in guiding treatment.

Precise treatment is a major pillar of modern medicine. An important aspect to enable accurate administration of treatment is complementing the accurate identification of the organ location that needs to be treated with a system and methods that ensure application of treatment only, or mainly to, that location. Imaging is off-course, a major component in such composite systems. Amongst the available solution, functional-imaging modalities are gaining traction. Specifically, molecular imaging (e.g. PET, MRS) allows the visual representation, characterization, and quantification of biological processes at the cellular and subcellular levels within intact living organisms. In oncology, it can be used to depict the abnormal molecules as well as the aberrant interactions of altered molecules on which cancers depend. Being able to detect such fundamental finger-prints of cancer is key to improved matching between drugs-based treatment and disease. Moreover, imaging-based quantified monitoring of changes in tumor metabolism and its microenvironment could provide real-time non-invasive tool to predict the evolution and progression of primary tumors, as well as the development of tumor metastases.

A recent review-paper: Image-guided interventional therapy for cancer with radiotherapeutic nanoparticles nicely illustrates the role of imaging in treatment guidance through a comprehensive discussion of; Image-guided radiotherapeutic using intravenous nanoparticles for the delivery of localized radiation to solid cancer tumors.

 Graphical abstract

 Abstract

One of the major limitations of current cancer therapy is the inability to deliver tumoricidal agents throughout the entire tumor mass using traditional intravenous administration. Nanoparticles carrying beta-emitting therapeutic radionuclides [DN: radioactive isotops that emits electrons as part of the decay process a list of β-emitting radionuclides used in radiotherapeutic nanoparticle preparation is given in table1 of this paper.) that are delivered using advanced image-guidance have significant potential to improve solid tumor therapy. The use of image-guidance in combination with nanoparticle carriers can improve the delivery of localized radiation to tumors. Nanoparticles labeled with certain beta-emitting radionuclides are intrinsically theranostic agents that can provide information regarding distribution and regional dosimetry within the tumor and the body. Image-guided thermal therapy results in increased uptake of intravenous nanoparticles within tumors, improving therapy. In addition, nanoparticles are ideal carriers for direct intratumoral infusion of beta-emitting radionuclides by convection enhanced delivery, permitting the delivery of localized therapeutic radiation without the requirement of the radionuclide exiting from the nanoparticle. With this approach, very high doses of radiation can be delivered to solid tumors while sparing normal organs. Recent technological developments in image-guidance, convection enhanced delivery and newly developed nanoparticles carrying beta-emitting radionuclides will be reviewed. Examples will be shown describing how this new approach has promise for the treatment of brain, head and neck, and other types of solid tumors.

The challenges this review discusses

  • intravenously administered drugs are inhibited in their intratumoral penetration by high interstitial pressures which prevent diffusion of drugs from the blood circulation into the tumor tissue [1–5].
  • relatively rapid clearance of intravenously administered drugs from the blood circulation by kidneys and liver.
  • drugs that do reach the solid tumor by diffusion are inhomogeneously distributed at the micro-scale – This cannot be overcome by simply administering larger systemic doses as toxicity to normal organs is generally the dose limiting factor.
  • even nanoparticulate drugs have poor penetration from the vascular compartment into the tumor and the nanoparticles that do penetrate are most often heterogeneously distributed

How imaging could mitigate the above mentioned challenges

  • The inclusion of an imaging probe during drug development can aid in determining the clearance kinetics and tissue distribution of the drug non-invasively. Such probe can also be used to determine the likelihood of the drug reaching the tumor and to what extent.

Note: Drugs that have increased accumulation within the targeted site are likely to be more effective as compared with others. In that respect, Nanoparticle-based drugs have an additional advantage over free drugs with their potential to be multifunctional carriers capable of carrying both therapeutic and diagnostic imaging probes (theranostic) in the same nanocarrier. These multifunctional nanoparticles can serve as theranostic agents and facilitate personalized treatment planning.

  • Imaging can also be used for localization of the tumor to improve the placement of a catheter or external device within tumors to cause cell death through thermal ablation or oxidative stress secondary to reactive oxygen species.

See the example of Vintfolide in The Role of Medical Imaging in Personalized Medicine

vinta

Note: Image guided thermal ablation methods include radiofrequency (RF) ablation, microwave ablation or high intensity focused ultrasound (HIFU). Photodynamic therapy methods using external light devices to activate photosensitizing agents can also be used to treat superficial tumors or deeper tumors when used with endoscopic catheters.

  • Quality control during and post treatment

For example: The use of high intensity focused ultrasound (HIFU) combined with nanoparticle therapeutics: HIFU is applied to improve drug delivery and to trigger drug release from nanoparticles. Gas-bubbles are playing the role of the drug’s nano-carrier. These are used both to increase the drug transport into the cell and as ultrasound-imaging contrast material. The ultrasound is also used for processes of drug-release and ablation.

 HIFU

Additional example; Multifunctional nanoparticles for tracking CED (convection enhanced delivery)  distribution within tumors: Nanoparticle that could serve as a carrier not only for the therapeutic radionuclides but simultaneously also for a therapeutic drug and 4 different types of imaging contrast agents including an MRI contrast agent, PET and SPECT nuclear diagnostic imaging agents and optical contrast agents as shown below. The ability to perform multiple types of imaging on the same nanoparticles will allow studies investigating the distribution and retention of nanoparticles initially in vivo using non-invasive imaging and later at the histological level using optical imaging.

 multi

Conclusions

Image-guided radiotherapeutic nanoparticles have significant potential for solid tumor cancer therapy. The current success of this therapy in animals is most likely due to the improved accumulation, retention and dispersion of nanoparticles within solid tumor following image-guided therapies as well as the micro-field of the β-particle which reduces the requirement of perfectly homogeneous tumor coverage. It is also possible that the intratumoral distribution of nanoparticles may benefit from their uptake by intratumoral macrophages although more research is required to determine the importance of this aspect of intratumoral radionuclide nanoparticle therapy. This new approach to cancer therapy is a fertile ground for many new technological developments as well as for new understandings in the basic biology of cancer therapy. The clinical success of this approach will depend on progress in many areas of interdisciplinary research including imaging technology, nanoparticle technology, computer and robot assisted image-guided application of therapies, radiation physics and oncology. Close collaboration of a wide variety of scientists and physicians including chemists, nanotechnologists, drug delivery experts, radiation physicists, robotics and software experts, toxicologists, surgeons, imaging physicians, and oncologists will best facilitate the implementation of this novel approach to the treatment of cancer in the clinical environment. Image-guided nanoparticle therapies including those with β-emission radionuclide nanoparticles have excellent promise to significantly impact clinical cancer therapy and advance the field of drug delivery.

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