Could we change the way we design our clinical trials to minimize failures?

We all hear from time to time that clinical trials fail sometimes, but the question today is why do they fail? And why should everyone know when something fails? Could we change the way we design our studies to minimize failures if we know why they fail?

Any regulations set for the clinical trials have a common goal to harmonize the procedures for clinical trials while making sure of the safety of clinical trial volunteers, the ethicality of trials and the dependability and productive effect of data derived. It advocates increasing reliability with regard to clinical trials results, data and their result. For life science companies, clinical trial information is highly of discreet affair which permeates a wide cultural evolution given that they operate in a very systematic and competitive environment, with lots of risk and profit.

The last few years, increasingly noticeable numbers of life science organizations have adopted a more free and transparent policy with regards to the results of their clinical trials, regardless of the positive or negative results.

From the recent past (March 2016) Celldex Therapeutics conducted a clinical trial on a brain tumor vaccine Rintega but the results were fruitless crushing its stocks. The organization announced the failure of Rintega Phase III study known as ACT UV after an interim analysis conducted by independent data monitors. The studies enrolled patients with certain type of Gliblastoma Multiforme (GBM), an aggressive brain tumor. Rintega was found to reduce the risk of death by just 1% compared to the control arm. However, at the median, Rintega-treated patients fared worse, surviving 20.4 months compared to 21.1 months for the control arm. Celldex is discontinuing clinical development of Rintega. Obviously, the company's plans to seek approval for the product in the U.S. or Europe are also being shelved. Celldex has two other drugs being tested on different clinical trials.

Cancer vaccines, particularly those targeting GBM, have a dismal track record. The failure of Rintega follows negative study results for ImmunoCelluar Therapeutics' GBM vaccine ICT-107. Northwest Biotherapeutics is developing a GBM vaccine known as DCVax, but a phase III study has been stalled since August due to an unexplained patient enrollment halt. There are other clinical trial failures too: Chrimex`s stocks also plunged recently after the failure of the clinical trial of an anti-infection drug in Phase III. [Dec-2015]. A French company`s [Bial] drug trial leaves on Brain dead and two others with permanent damage, there is no known antidote as the drug was never used on human before this trial. There is a 50% probability for every clinical trial to fail.

There are three root causes of clinical trial failures:

A. Molecule issues
When the molecule, doesn’t have sufficient biological activity or doesn’t have manageable toxicity. A well-designed clinical program can pick up the side activity and the program can be redirected. But if the molecule has no biological activity when it enters clinical development, only little can be done to salvage it. Just as important are predictability and pervasiveness of the unmanageable toxicity. Every molecule has toxicity but it is important to design a clinical trial accordingly around them.

B. Logistic issues
Half of the published preclinical experiments may be unreproducible. In the hurry to get the clinical trial started, sometimes sponsors neglect to triple-check the randomization algorithm. Despite validation, mistakes in data analysis programming can occur. Many companies don’t double program (have two sets of independent programmers or program two full sets of analysis independently) and in that case, it is almost inevitable there will be mistakes somewhere.

C. Study design issues
Error in clinical trial design is perhaps the most common reason trials fail, other than the above two reasons. There are many variables in clinical trial design but of those, three are the most important when it comes to insuring a successful clinical trial:

• Selecting the right patients
• Patient selection can go awry if the selection blindly follow the conventional disease categories and definitions. There are many ways to define patient populations and diseases. It is not always optimal to define the patient population by a previously recognized disease category because disease categories are intellectual constructs

• Selecting the right dosing
• All the characteristics of the dose, including: the amount of an intervention administered, the route of administration (e.g., oral, IV, SC), the dosing interval, the rate and duration of administration.
• Frequently seen error is using a dosing regime that is too undifferentiated, such as a flat dose. When great heterogeneity in patient response or a narrow therapeutic window exists, you may have to customize the dose.

• Selecting the right endpoint

• Clinically relevant
• Closely and comprehensively reflects overall disease being treated
• Rich in information
• Responsive (sensitive, discriminating, and has good distribution)
• Reliable (precise, low variability, and is reproducible) even across studies
• Robust to dropouts and missing data
• Does not influence treatment response or have biological effect in and of itself
• Practical (implementable at different sites, measurable in all patients, economical, and reasonably noninvasive)

Often, a drug has biological activity but it is tested for the wrong indication. Or, it is tested in the right indication but in the wrong sub-populations. In other instances, the wrong dose or dose interval is selected. It is therefore kept in mind that sometimes the most expensive testing studies fail for various reasons leaving long lasting scientific and trading loss.

References
 http://www.thestreet.com/story/13484143/1/celldex-brain-tumor-vaccine-fails-pivotal-clinical-trial.htm
 http://www.celldex.com/pipeline/rindopepimut.php lhttps://clinicaltrialist.wordpress.com/clinical/why-clinical-trials-fail/
 https://www.theguardian.com/science/2016/jan/15/six-volunteers-in-hospital-after-unprecedented-accident-in-french-drug-trial
http://www.xconomy.com/raleigh-durham/2015/12/28/chimerix-stock-plunges-after-anti-infection-drug-fails-phase-3-trial/#

Written by Shalini P. Burra for The All Results Journals. 

Negative results of bapineuzumab clinical trials may question the basis of Alzheimer’s disease

After several years of clinical testing, Pzifer and Johnson&Johnson recently announced that one of their most promising drugs to treat Alzheimer’s, bapineuzumab, has failed to meet primary endpoints in a phase III trial. As a consequence, not only 130 positions have been eliminated, but also the molecular basis of this neurodegenerative disease itself has been questioned.

The drug consists of a monoclonal-humanised antibody against beta-amyloid, a toxic protein for the brain whose accumulation is believed by many scientists to be responsible for the degenerative changes associated with this illness. The immunotherapy seemed the perfect solution in order to clear the build-up of amyloid plaques or prevent its formation, as the binding of the antibodies to the plaques should be able to remove them from the brain, thus improving the cognition or daily functioning of the patients.

The intravenous formulation of bapineuzumab was tested on 1,100 people with mild-to-moderate disease. Moreover, all of them carried the ApoE4 genotype (about half of the Alzheimer’s population shares this genotype), which raises the risk of suffering from Alzheimer’s and may also worsen its symptoms. Although in early phase II trials performed on 2008 the drug did not show significant effects, they decided to keep on testing due to the promising theoretical benefits of this kind of treatment. However, in phase III trials patients who took the drug did not significantly outperform the placebo.

The negative results of the trial could suggest that beta-amyloid might not be the culprit in Alzheimer’s disease. Alternatively, some experts think there could be another reason behind this failure: the drug may have been administrated to people at a late stage of the disease. Yet, this statement doesn’t make any sense; if amyloid is in fact the toxic component, an effective anti-amyloid immunotherapy should succeed in slowing disease progression. Besides, there is a phase I case report published in The Lancet (Amyloid-β vaccination for Alzheimer's dementia, 2008) of an anti-amyloid vaccine in which the authors did not observe prevention of progressive degeneration despite of the clearance of amyloid plaques.

All in all, the publication of this negative result is expected to be a turning point with regard to the molecular basis of the disease; the amyloid hypothesis is probably dead for the moment.

References:
1.- Ed Silverman (October 2012) J&J Cuts 130 Jobs After Alzheimer Drug Fails. Pharmalot.
2.- Michelle Castillo (July 2012) Anticipated Alzheimer's drug bapineuzumab shows no patient benefits in trial. CBSNews.
3.- Nathan Sadeghi-Nejad (July 2012) The Lessons Of Failure: What We Can Learn From Bapineuzumab's Blowup. Forbes.
4.- doi:10.1016/S0140-6736(08)61580-9
5.- doi: 10.1212/WNL.0b013e3181c67808

Written by Julio Rios for The All Results Journals.

New research reveals antibiotics may be used for retreatment of Lyme disease

According a new statistical review, retreatment can be beneficial for Lyme disease (Lyme borreliosis). This research published by Brown University, shows that the last known studies about this illness were wrong. Four studies, upon which Lyme retreatment guidelines are based, report flaws in design, analysis, and interpretation that call into question the strength of the evidence against retreatment.

Until now, most doctors treat Lyme disease with a two to four week course of antibiotics. But if symptoms persist after that, medical guidelines recommend against antibiotic retreatment. It seems this is all subject to change.

Allison DeLong, a biostatistician at Brown University's Center for Statistical Sciences, has published a study questioning Lyme retreatment guidance. Lyme disease is caused by the tick-borne spirochete ‘Borrelia burgdorferi’. Long-term persistent illness following antibiotic treatment is not uncommon, particularly when treatment is delayed. Current treatment guidelines for persistent disease primarily rely on findings from four randomized, controlled trials (RCTs), strongly advising against retreatment.

For DeLong, the four studies do not prove that retreatment does not work: “a lack of evidence should not be used to deny treatment when the studies have serious flaws”, she said. DeLong and three co-authors found evidence in the trials are, more often than not, inconclusive.

Dr DeLong had been concerned about Lyme disease for over a decade; it was not until 2009 when she and her colleagues decided to look into the matter with full statistical rigor. The most influential studies were conducted by Klempner et al., and published together in the New England Journal of Medicine in 2001.

The multicenter trials enrolled chronic Lyme sufferers, patients either received intra-venous antibiotics followed by oral antibiotics or an intra-venous placebo followed by an oral placebo. Klempner and colleagues found no significant benefit to retreatment. “Klempner's statistics showed that treatment might or might not have been effective given the broad range of statistical measure known as the confidence interval”, DeLong said.

In another of the four trials conducted by Krupp et al., researchers found that retreatment produced a significant benefit for fatigue, but the authors of the study mistakenly discounted that result. The authors became concerned that their results were tainted by too many subjects realizing that they were receiving real treatment instead of the placebo. The measure of fatigue is subjective and could be influenced by that realization. But DeLong found that the subjects weren't likely to have realized anything.

“Ultimately”, DeLong said, “the best evidence to support or refute antibiotic retreatment will come when scientists develop a definitive test for active Lyme disease infection.” In the interim, it is possible that chronic Lyme disease patients harbor an ongoing infection that antibiotics could treat.

Written by Alejandro Balbuena for The All Results Journals. 

 

New editorial board member

SACSIS is delighted to announce the opening of a new section (Particle Physics) at The All Results Journals: Phys and the appointment of Professor Ehud Duchovni as new section editor on the Editorial Board.

Prof. Duchovni (PhD) is Associate Professor at Department of particle physics and astrophysics at the Weizmann Institute of Science, Rehovot, Israel. He obtained his Ph.D in this department for his work on di-jet production in photon-photon collisions.

Presently, he heads the Weizmann team participating in the ATLAS experiment at CERN and is a member in the Xenon experiment at LNGS.

At ATLAS his work is focused on the search for new phenomena in general, and for supersymmetric signals in particular. At Xenon he is engaged in the search for weakly interacting particles (WIMP). He is serving as an editor in JINST, and in various capacities at Israel and CERN.

More information can be found at his laboratory website.

New editorial board member

SACSIS is delighted to announce the opening of a new section (Pharmaceutical Science) at The All Results Journals: Biol and the appointment of Professor D. Nagasamy Venkatesh as new section editor on the Editorial Board.

Dr. Venkatesh (PhD) is Assistant Professor at Department of Pharmaceutics, JSS College of Pharmacy, (A Constituent College of JSS University, Mysore) Ooty, South India. He obtained his Ph.D in Faculty of Pharmacy from the Tamil Nadu Dr. MGR Medical University, Chennai, India for his topic Formulation and Development of sustained release dosage form for selected drug candidates.
 
Presently, he is working in the areas of development of nanoparticle-mediated drug delivery for certain anticancer agents, antiviral agents, anti-diabetic agents, development of controlled/sustained release tablets for certain drugs and dissolution enhancement of certain drugs by solid dispersion technology.

He is serving as editorial/advisory board member and paper reviewer for many peer reviewed international and national journals. He is a life member of Indian Pharmaceutical Association, Nilgiris Local Branch, Association of Pharmaceutical Teachers of India and annual member in controlled release society, Indian Chapter.

New volunteer in The All Results Journals

The All Results Journals: Biol is having Dr. Syed M. Nurulain [B.Sc. (Hons), M.Sc., M.Phil. and PhD] as a new volunteer.

Dr. Nurulain is working in The Faculty of Medicine and Health Sciences, United Arab Emirates University, as Medical Research Specialist. Dr. Nurulain's area of research is focus on in vivo toxicology in rodent model, teratology, in vitro toxicology, pharmacokinetics, oximes efficacy, electrophysiology (voltage gated ion channels) and diabetes rat models, with more than forty research articles published in the field.

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You can also collaborate with SACSIS as volunteer in several tasks:


* Editorial assistant for The All Results Journals
* Scientific Copyeditors
* English proofreader
* Marketing (online and off-line)
* Scientific journalism
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* Active participation within the organization, design, evaluation and programming of the activities.
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New volunteer in The All Results Journals

The All Results Journals: Chem is having Dr. Amparo Ruiz Carretero as a new volunteer. Dr. Ruiz Carretero is an organic chemist working as a postdoctoral fellow at Northwestern University in Chicago (Illinois). Her research is directed towards the use of self-assembly in energy technologies such as organic photovoltaics.

Welcome to SACSIS team!

You can also collaborate with SACSIS as volunteer in several tasks:


* Editorial assistant for The All Results Journals
* Scientific Copyeditors
* English proofreader
* Marketing (online and off-line)
* Scientific journalism
* Web development
* Scientific writer
* Reviewer of The All Results Journals
* Fundraising

SACSIS will provide the volunteer:

* The information, training, support and the material necessary to exercise the functions assigned to it.
* Active participation within the organization, design, evaluation and programming of the activities.
* Opportunities for professional development and social interaction with other volunteers.


For a better understanding of what you can expect as a volunteer and what is expected of you by our organization, please contact us with a brief note about your interests at: 

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New editorial board member

SACSIS is delighted to announce the opening of a new section (Clinical Studies) at The All Results Journals: Biol  and the appointment of Professor Felipe Fregni as new section editor on the Editorial Board.

Felipe Fregni (MD, PhD, MPH), is the Director of the Laboratory of Neuromodulation at Spaulding Rehabilitation Hospital, Harvard Medical School, as well as an Associate Professor of Neurology and Physical Medicine and Rehabilitation at Harvard Medical School, Boston, MA, USA.
He is also the course director for the HMS continuing medical education course, Principles and Practice of Clinical Research, a 6-month distance learning course. It focuses on promoting collaboration and bringing clinical research education to practicing clinicians worldwide.

Currently, his research is focused on understanding neuroplastic changes associated with conditions such as chronic pain, Parkinson’s disease, and stroke, using non-invasive brain stimulation as an investigative tool for such aims. In addition, his laboratory is comprised of about 15 research fellows and staff, and is a training center for clinical research and neuromodulation methodology.

Dr. Fregni’s laboratory is funded by several sponsors including NIH, the Christopher and Dana Reeve Foundation, CIMIT, and the RJG Foundation. More information can be found at his laboratory website, www.neuromodulationlab.org.

New volunteer in The All Results Journals

The All Results Journals: Biol is having Dr. Francisco Fernández Campos as a new volunteer. Dr. Fernández is Assistant Professor at the Biopharmaceutical and Pharmacokinetics Unit of the University of Barcelona (Faculty of Pharmacy). His research is focused in the field of drug delivery systems (in vivo and in vitro behavior).

Welcome to SACSIS team!

You can also collaborate with SACSIS as volunteer in several tasks:


* Editorial assistant for The All Results Journals
* Scientific Copyeditors
* English proofreader
* Marketing (online and off-line)
* Scientific journalism
* Web development
* Scientific writer
* Reviewer of The All Results Journals
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SACSIS will provide the volunteer:

* The information, training, support and the material necessary to exercise the functions assigned to it.
* Active participation within the organization, design, evaluation and programming of the activities.
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For a better understanding of what you can expect as a volunteer and what is expected of you by our organization, please contact us with a brief note about your interests at: 

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New Editorial Board Member

SACSIS is delighted to announce the appointment of Professor Ron van Noorden as new member of The All Results Journals: Biol Editorial Board.


Prof. van Noorden was born in 1951 and is the chairman (1993-present) of the Department of Cell Biology and Histology of the Academic Medical Center at the University of Amsterdam.  He obtained the PhD in 1983 at the University of Amsterdam. After that, he got appointments as a  lecturer (1983-1986), associate professor (1986-1997) and full professor in cell biology and histology (1997-present). He was selected by the students as lecturer of the year twice in the curriculum Medical Informatics (in 1998 and 1999) and twice in the curriculum Medicine (in 2003 and 2004) at the AMC.


Van Noorden's research was always focused on activity of proteins and particularly enzymes in their natural microenvironment, the cell or the extracellular matrix, in pathophysiological conditions such as arthritis, invasion and metastasis of cancer and now brain tumors (glioblastoma) and blindness due to diabetes (diabetic retinopathy).

Prof. van Noorden have published more than 300 peer reviewed papers and has been promotor of 27 PhD students. He won the Robert Feulgen Prize of the Society for Histochemistry in 1987 together with Roger Butcher for their contribution to quantitative analysis of enzyme activity in situ.  He presented the first Piet Van Duijn Lecture of the Dutch Foundation Histochemistry in Kyoto, Japan, 1996 on live cell imaging and in 2008 he won the David Glick Award of the International Federation of Societies for Histochemistry and Cytochemistry.

New editorial board member

SACSIS is delighted to announce the appointment of Professor Gerhard Flachowsky as new member of The All Results Journals: Biol Editorial Board.


Prof. Gerhard Flachowsky was born in 1944 (Stangendorf, Germany) and has been the Director of the Institute of Animal Nutrition at Braunschweig (Germany) till 2009. He obtained the PhD in 1971 at the University of Jena. After that, he got his habilitation in 1979 (University Leipzig, Germany) and an appointment as full professor of Animal Nutrition at the University Jena in 1989. In 1994 became the Director of the Institute of Animal Nutrition at Braunschweig.


Prof. Flachosky's research is focused on:

• Nutritional physiology
• Ruminant nutrition
• Feed sciences (including feed additives, nutritional and safety assessment of feeds)
• Animal nutrition and quality of animal products/environment
• Nutrient economy.

Prof. Flachosky have published more than 500 peer reviewed papers and has been member of the Scientific Committee of Animal Nutrition (SCAN) of the EU (1997-2003) and of the FEEDAP-Panel of the European Food Safety Authority (EFSA, 2003-2006). Since 2002 he is working as expert for animal nutrition in Working groups of the GMO-Panel of the EFSA and since 2009 works as a member of the Panel on Genetically Modified Organisms (GMO-Panel) of the EFSA. He is the Chairman of the Committee of Nutrient Requirements (AfBN) in the Society of Nutritional Physiology, Germany (since 2000), President of the FAL (2002/2003) and was President of the Senate of all Federal Agricultural Research Institutes in Germany (2004-2006).

New Editorial Board Member

SACSIS is delighted to announce the appointment of Professor George Perry as new member of The All Results Journals: Biol Editorial Board.

Prof. Perry is a neuroscientist, Dean of the College of Sciences and Professor of Biology at the University of Texas at San Antonio. He obtained his PhD in Marine Biology under David Epel in 1979. He then received a postdoctoral fellowship in the Department of Cell Biology in the laboratories of Drs. Bill Brinkley, Joseph Bryan and Anthony R. Means at Baylor College of Medicine where he laid the foundation for his observations of cytoskeletal abnormalities. He is also distinguished as one of the top 20 Alzheimer's disease researchers with over 800 publications, one of the top 100 most-cited scientists in Neuroscience & Behavior and one of the top 25 scientists in Free Radical research . He currently serves as a President for the American Association of Neuropathologists.

Perry's research is primarily focused on the mechanism of formation and physiological consequences of the cytopathology of Alzheimer disease. He has played a key role in elucidating oxidative damage as the initial cytopathological abnormality in Alzheimer disease. He is currently working to determine the sequence of events leading to neuronal oxidative damage and the source of the increased oxygen radicals. His current studies focus on two issues: (i) the metabolic basis for the mitochondrial damage restricted to vulnerable neurons; and (ii) the consequences of RNA oxidation on protein synthesis rate and fidelity.

New volunteer in The All Results Journals

The All Results Journals: Nano is having Dr. Olga Maritnez as a new volunteer. Dr Martinez-Avila is a material scientist at the Division of Biomaterials and Bioengineering at University of California San Francisco, in the Preventive and Restorative dental sciences at the Dental School.

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You can also collaborate with SACSIS as volunteer in several tasks:


* Editorial assistant for The All Results Journals
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* Marketing (online and off-line)
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* The information, training, support and the material necessary to exercise the functions assigned to it.
* Active participation within the organization, design, evaluation and programming of the activities.
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For a better understanding of what you can expect as a volunteer and what is expected of you by our organization, please contact us with a brief note about your interests at: 

secretary@arjournals.com

New volunteer in The All Results Journals

The All Results Journals: Chem is having Dr. Dingbang Xiong as a new volunteer. Dr. Xiong is now a JSPS research fellow at Kyoto University and focuses his research on the development of new thermoelectric materials.

Welcome to SACSIS team!

You can also collaborate with SACSIS as volunteer in several tasks:


* Editorial assistant for The All Results Journals
* English proofreader
* Marketing (online and off-line)
* Scientific journalism
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* Scientific writer
* Reviewer of The All Results Journals
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SACSIS will provide the volunteer:

* The information, training, support and the material necessary to exercise the functions assigned to it.
* Active participation within the organization, design, evaluation and programming of the activities.
* Opportunities for professional development and social interaction with other volunteers.


For a better understanding of what you can expect as a volunteer and what is expected of you by our organization, please contact us with a brief note about your interests at: 

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New volunteer in The All Results Journals

The All Results Journals is having Dr. Victoria Valdivia as a new volunteer. Dr. Valdivia is a organic chemist at the department of chemical and pharmaceutical sciences at the University of Trieste (Italy), in the Carbon Nanotechnology group.

Welcome to SACSIS team!

You can also collaborate with SACSIS as volunteer in several tasks:


* Editorial assistant for The All Results Journals
* English proofreader
* Marketing (online and off-line)
* Scientific journalism
* Web development
* Scientific writer
* Reviewer of The All Results Journals
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SACSIS will provide the volunteer:

* The information, training, support and the material necessary to exercise the functions assigned to it.
* Active participation within the organization, design, evaluation and programming of the activities.
* Opportunities for professional development and social interaction with other volunteers.


For a better understanding of what you can expect as a volunteer and what is expected of you by our organization, please contact us with a brief note about your interests at:

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New Volunteer in The All Results Journals:Chem

The All Results Journals: Chem is having Dr. Mark Karver as a new volunteer. Dr. Karver is a chemist at CSB (Massachusetts General Hospital/Harvard Medical School) and a member of scientific societies such as ACS or MGPA.

Welcome to SACSIS team!

You can also collaborate with SACSIS as volunteer in several tasks:


* Editorial assistant for The All Results Journals
* English proofreader
* Marketing (online and off-line)
* Scientific journalism
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SACSIS will provide the volunteer:

* The information, training, support and the material necessary to exercise the functions assigned to it.
* Active participation within the organization, design, evaluation and programming of the activities.
* Opportunities for professional development and social interaction with other volunteers.


For a better understanding of what you can expect as a volunteer and what is expected of you by our organization, please contact us with a brief note about your interests at:

secretary@arjournals.com