New Project Aims to Set Effectiveness Guidelines for Hemophilia Gene Therapy Trials


New Project Aims to Set Effectiveness Guidelines for Hemophilia Gene Therapy Trials

An international team has joined efforts to establish guidelines for effectiveness and outcome measurements regarding gene therapies in hemophilia.

The CoreHEM project will be led by researchers from McMaster University in Ontario, Canada, in collaboration with the National Hemophilia Foundation (NHF) in the U.S. and the Green Park Collaborative — a major initiative of the Center for Medical Technology Policy (CMTP), based in Baltimore, Maryland.

“With a growing pipeline of gene therapy products for hemophilia, it is an ideal time for this work,” Sean Tunis, president and CEO of CMTP, said in a news release. “This effort will potentially serve as a model for achieving consensus around outcomes to demonstrate effectiveness and value for promising emerging therapies in many other clinical areas, as well as for other rare conditions.”

Hemophilia is caused by a genetic defect that leads to low levels or the total absence of clotting factors — factor VIII in hemophilia A and factor IX in hemophilia B — which are necessary for effective bleeding control. Hemophilia patients need to receive routine injections of the missing clotting factors to control symptoms of the disease. This demanding therapy schedule can have an extreme impact on patients’ quality of life.

Scientific advances have led to the development of new treatments that may have the potential to cure hemophilia A and B by replacing the damaged gene. Clinical trials on these new gene therapies should provide enough evidence demonstrating their effectiveness, but also substantial improvements in reducing or eliminating burdens of the disease.

The CoreHEM project aims to define a core outcome, set through a consensus process, which should be considered when evaluating the effectiveness of gene therapies in patients with hemophilia.

Taking into consideration input from patients, clinicians, researchers, product manufacturers, public and private payers, and U.S. and international government agencies, the team will create a list of potential outcome domains and measurement approaches that will be reviewed by a steering committee.

This list will go through an online Delphi voting process and an in-person consensus meeting to prioritize and condense the list into the final core outcome set.

“These breakthroughs have the potential to be life-changing,” said Val Bias, CEO of the National Hemophilia Foundation. “This collaborative effort will bring a much needed voice from our patients, and the important role they play in identifying outcomes that are vital to their health.”

The final results of the CoreHEM project, expected early in 2018, will be published in a peer-reviewed article providing recommendations for important patient outcomes in clinical studies focused on gene therapies for hemophilia. In addition, an “effectiveness guidance document” will also be published.

Implementing these outcome-defined measures will not only help patients and clinicians to make better treatment-related decisions, but will also potentially improve the way clinical trials are conducted and assessed.

“The enthusiasm from so many stakeholders to becoming part of the project speaks volumes to the potential of this initiative,” said Alfonso Iorio, co-principal investigator and associate professor of health research methods, evidence, and impact at McMaster University.

Creating a consensus for implementation early in the development of breakthrough technology is a key to success, he added.

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Novel Methods and Technologies for 21st-Century Clinical Trials


Importance  New technologies are rapidly reshaping health care. However, their effect on drug development to date generally has been limited.

Objectives  To evaluate disease modeling and simulation, alternative study design, novel objective measures, virtual research visits, and enhanced participant engagement and to examine their potential effects as methods and tools on clinical trials.

Evidence Review  We conducted a systematic search of relevant terms on PubMed (disease modelingand clinical trials; adaptive design, clinical trials, and neurology; Internet, clinical trials, and neurology; and telemedicine, clinical trials, and neurology), references of previous publications, and our files. The search encompassed articles published from January 1, 2000, through November 30, 2014, and produced 7976 articles, of which 22 were determined to be relevant and are included in this review.

Findings  Few of these new methods and technologies have been applied to neurology clinical trials. Clinical outcomes, including cognitive and stroke outcomes, increasingly are captured remotely. Other therapeutic areas have successfully implemented many of these tools and technologies, including web-enabled clinical trials.

Conclusions and Relevance  Increased use of new tools and approaches in future clinical trials can enhance the design, improve the assessment, and engage participants in the evaluation of novel therapies for neurologic disorders.

How to Get All Trials Reported: Audit, Better Data, and Individual Accountability


In this week’s PLOS Medicine, the World Health Organization (WHO) publishes a landmark position statement, requiring all trials to make their methods and results available [1]. This represents important progress on a long-standing and global structural problem that has a clear, negative impact on patient care. The best currently available evidence shows that the methods and results of clinical trials are routinely withheld from doctors, researchers, and patients [25], undermining our best efforts at informed decision making. From this point forward, whenever the methods and results of a trial are withheld, doctors, patients, researchers, campaigners, and health care providers will be able to point at an unambiguous statement from WHO.

Delivering definitive change, however, will require more than positive statements and good intentions. The first quantitative data demonstrating publication bias in clinical trials—and clear call for trial registries—was published in 1986 [6]. Anyone withholding the methods and results of a clinical trial is already in breach of multiple codes and regulations, including the Declaration of Helsinki, various promises from industry and professional bodies, and, in many cases, the United States Food and Drug Administration (FDA) Amendment Act of 2007. Indeed, a recently published cohort study of trials in clinicaltrials.gov found that more than half had failed to post results; and even though the FDA is entitled to issue fines of $10,000 a day for transgressions, no such fines have ever been levied [3].

In the face of such slow progress, this commentary sets out some practical suggestions for auditing, performance tables, accountability, codes of conduct, and better data that should help to drive up standards and prevent trial reports being withheld from those who need them most.

What Should Trials Transparency Look Like, and How Do We Achieve It?

The WHO statement calls for summary results to be both posted on a registry and submitted to a journal within 12 months. However, it is worth noting that academic journal publication may ultimately prove to be a red herring, as an indicator of transparency. Academic publishing decisions can be arbitrary, and introduce lengthy delays in access to knowledge. Furthermore, there is a growing body of evidence demonstrating that journals often fall short of the basic expected standards for reporting of clinical trials. It is commonplace to find that primary outcomes have been switched, for example [7]; findings are routinely “spun” [8]; and compliance with reporting standards such as CONSORT is highly variable. When compared with the long and formal structured Clinical Study Reports created for all industry-sponsored trials, academic papers have been shown to be incomplete and inconsistent [9].

However, since all clinical trials are fundamentally similar—when compared, for example, with the myriad study designs in molecular biology—it has been possible to develop reporting standards and operationalise these. Reporting results onto a structured database, such as the results tab of clinicaltrials.gov [10], has many preferable features: there is minimal delay, there is compulsory reporting of features that are required; and there is no possibility to switch pre-specified outcomes or other forms of reporting misconduct. Put simply, there is a box to report the pre-specified primary outcome, and it has to be filled. Recent research has shown that academic journal reports are inconsistent with those on clinicaltrials.gov [2] and contain less complete information on methods, results, and adverse events [11]. Furthermore, International Committee of Medical Journal Editors (ICMJE) member journals have explicitly stated that they will not reject trial reports on the grounds that the results have already appeared on clinicaltrials.gov, and that they do not regard registry results reporting as prior publication [12]. Lastly, clinicaltrials.gov is clear that they will accept results on any trial, from any era, on any treatment, from any territory. This negates a key defence commonly cited by trialists and sponsors when facing calls for greater transparency: that journals reject “negative” results. All trials can now be reported, immediately, using clinicaltrials.gov as a first or last resort, if the trialist is willing. The question remains: how can we ensure this is done?

The Need for Audit

One key element is likely to lie in medicine’s most basic research tool. Audits are routinely conducted on local service issues, such as infection rates, or waiting times, but rarely on broader structural issues such as publication bias, even though the impact of the latter on patient care is likely to be greater and global. Indeed, it is peculiar that for many years trial registration was considered an end in itself, when in reality registration is only of value as the raw material for publication audit.

The basic structure for a routine ongoing audit of results reporting is simple: using a register, identify trials that completed more than 12 months ago; establish, through whatever means, whether results from the trial have been reported; and post the date of results appearing to the register. From this, it is trivial to derive performance metrics for individual companies, funders, drugs, disease areas, institutions, and investigators.

This is highly specific and accountable information that can be used for practical good. Firstly, the very act of creating such data would allow us to name and shame poor performers, and also to reward best practice. Furthermore, those falling behind can identify and learn from those who are successfully meeting their obligations to patients.

The results of the audit can also be used to inform medical decision making. While it is unwise for doctors to use their prescription pads to pursue political goals, transparency metrics for an individual drug company are valuable context for interpreting data on the benefits of their products. For example, suppose there are two treatments of apparently equal benefit in meta-analysis, but one is made by a company with a proven track record of complete transparency, with 95% of all information available, while the other is made by a company with clear record of withholding information. The clinically cautious approach is to prescribe the treatment for which the results are more reliable, from the company that is more transparent.

Audit data can also be used by ethics committees and institutional review boards (IRBs). Withholding the results of clinical trials is unethical and harms patients. Those guilty of such misconduct could be banned from conducting further trials on patients until their previous trials have been made available. Indeed, even in the absence of such audit data, it would be trivial for all IRBs to ask one simple question of all those applying to conduct a trial: “Have you been involved in any clinical trial, which completed more than 12 months ago, for which the results remain inaccessible?”

Professional bodies and professional regulators, similarly, can now incorporate the WHO guidance into their codes of conduct and create mechanisms to ensure it is acted upon, for example by opening formal investigations when contacted over concerns around results being withheld by individual researchers or clinicians, and triggering disciplinary action whenever audit shows that the codes have been broken. It is rare, in professional regulation, to have data on transgressions created so rapidly and so unambiguously; it would be wrong to neglect this opportunity to improve standards. Patient groups, lastly, could write open letters to all companies and researchers withholding methods and results of trials on treatments taken by their members, represent their constituencies by holding individuals to reasonable account, and again help improve compliance.

The Practicalities of Audit

Such audit can be conducted locally, centrally, or ideally, both. Since the recent rejuvenation in policy discussion in the United Kingdom on withheld trials, there have been small local audits conducted by various bodies, including sections of the Health Research Authority (as yet unpublished); the National Institute of Health Research (as yet unpublished); the Medical Research Council (to produce an estimate of publication bias for a 2012 UK parliamentary inquiry into trials transparency [13], but as yet unpublished); and an ongoing audit, on which I am a collaborator, covering trials in the University of Oxford. For the latter, alongside our findings, we also plan to publish our practical experiences of conducting the audit, with a boilerplate protocol that can be used by others in order to help make local audits simpler and produce comparable data. Such audits could and should be conducted and published routinely by all government research funders, industry sponsors, and institutions, to help ensure that all trials are reported.

Central audit is also desirable, and can be readily worked into existing trial registry workflows. At present, a completed trial without an associated results report on a registry may represent a transgression, but it may also represent an administrative failure. Publishing performance data and acting upon it will incentivise trialists to update their records. Worse still, it is currently impossible to establish on clinicaltrials.gov whether a completed trial has successfully requested an extension for reporting (whatever one might think of such exemptions), because this information is not posted; if data fields on such exceptions are routinely and transparently posted in public onto the database, compliance and transparency rankings can be automatically generated at no cost.

When discussing efficiencies, it is important to be clear, however, that the cost of even manual audit is trivial in comparison to the cost of conducting a randomised trial. Producing accessible knowledge for clinical decision making is the key purpose of a trial. Once a trial has been conducted—at great cost—and left unreported, then the small and final marginal cost of making its results available represents better value for money than almost any other step in the research process.

What to Do about Past Trials

The emphasis by WHO on having access to all trials, from the past as well as the future, is particularly important and welcome. It is clinically highly relevant because the overwhelming majority of prescriptions today are for treatments that came onto the market—and were therefore researched—over the preceding decades rather than the past five years. The question, however, is how to prioritise access to such information, since there is no sense in resources being deployed on sharing evidence that is no longer relevant to current practice. There are many options. One is to proactively release information, prioritising by some metric of clinical need, such as the number of patients affected; or usage, such as the number of prescriptions issued for that class of treatments; or even a complex model built around power calculations and the likelihood of the withheld data changing the conclusions of the best current systematic review.

A simpler option, however, is for thorough retrospective registration of clinical trials to act as a “menu” from which doctors, researchers, and patients can request further disclosure of full methods and results, with appropriate transparency around the request and adjudication process. This is an attractive option since registration is low cost, but it does present one previously undocumented challenge. Through the AllTrials.net campaign, we are currently conducting an audit of companies’ policies on trials transparency, to create a Trials Transparency Index. In doing so, we have met a large number of individual companies to ask about gaps in their policies. One recurring theme, on the issue of retrospective registration, is that registries often require detailed administrative information (such as an IRB approval number) that is not readily traceable 20 years after a trial was completed. It may therefore be pragmatic to take a more permissive approach to completeness of certain data fields, with missing items replaced by an explanatory note where absolutely necessary, in preference to a trial not being retrospectively registered at all.

Conclusion

The position statement from WHO is powerful and welcome, but previous calls for registration were not enough to fix publication bias, and positive statements require practical implementation. The solution is likely to lie in simple audit, providing better data for individual accountability. This can be delivered at low cost through a routine audit cycle to identify completed but unreported trials on all registries, with public performance tables that will incentivise trialists to ensure their registry entries reflect their compliance. Local audit will facilitate data-checking and ensure local accountability. As with all audit cycles throughout clinical practice this data must be acted on, with those who are guilty of research misconduct in withheld trials exposed to public scrutiny and local performance management; investigations automatically triggered by their professional regulators; and denied access to further trial participants. Lastly, doctors and patients can act on withheld data exposed by audit and consider avoiding treatments—or indeed whole companies—where there is clear evidence that the data on those interventions is comparatively unreliable.

These are simple processes that should have been integrated into the information ecosystem of evidence-based medicine from the outset. We cannot make truly informed decisions when vitally important information on the methods and results of clinical trials is routinely withheld, and yet we have tolerated this simple, fixable, pervasive flaw in evidence-based medicine for many decades. The doctors and patients of the future may well look back on this phenomenon with amazement, much as we look back on mediaeval bloodletting.

Plaque-fighting Drug Passes Early Clinical Test in Humans


On March 20, from a conference in France, the Cambridge, Mass.-based biotech company,Biogen Idec reported success in the PRIME trial, an early clinical trial of its Alzheimer’s drug, aducanumab. Results proved “better than expected,” the company said, from its phase 1 trial enrolling 166 subjects with prodromal-to-mild Alzheimer’s. Individuals treated with aducanumab had a significant reduction in amyloid and symptoms of cognitive impairment were slowed compared with untreated controls.

“Prodromal” Alzheimer’s is also referred to asmild cognitive impairment (MCI). On the continuum leading up to Alzheimer’s, it lies between preclinical Alzheimer’s, when it’s possible to detect biochemical changes associated with disease but no changes in cognition, and mild Alzheimer’s, where cognitive decline from Alzheimer’s begins to have an impact on mood and functioning. Not all people with MCI progress to Alzheimer’s.

These trial results, while promising, are among the earliest attempts to test aducanumab in humans,and have to be viewed with caution. Phase 1 trials are deliberately small and narrow in scope, designed to assess safety and establish safe dosing levels for promising agents as they head out of the starting gate. From a safety standpoint, aducanumab appears to be safe, although side effects were reported at higher dosing levels. These concerns will be analyzed further in data from this trial, and from phase 3 trials up ahead, which the company has announced it will pursue.

Phase 3 trials are considered the gold standard proof of clinical effectiveness, and are meant to test a drug’s effectiveness over time in the patient population it’s designed to treat. If successful, they typically lead to a drug’s approval by the U.S. Food and Drug Administration, at which point companies are free to market their product for specific conditions under a brand name.

New Hope—Could This Be the Dawn of Disease Modifying Therapies?

Aducanumab’s early success may signals a turn in the tide for anti-amyloid therapy. A New York Times story suggested as much, but also cataloged earlier, failed trials of similar agents. They included a joint effort by the pharmaceutical giants Johnson & Johnson and Pfizer to develop a plaque-fighting drug, which was abandoned at the clinical trial stage due to poor results. Disappointing early results also forced the Swiss pharmaceutical, Roche, to close a phase 3 trial of its anti-amyloid agent gantenerumab; however, development efforts are said to be ongoing.

Graph showing how brain functin, vascular regulation, and neuropathology change during the latent, prodromal, and disease phase of Alzheimer's.

It’s believed that anti-amyloid therapies will be most effective when they attack the disease early. Preclinical (“latent”) and prodromal stages can last as long or longer than the “disease stage” shown above, meaning after Alzheimer’s is diagnosed, when clinical symptoms are evident. In the build-up to that point, it may be possible to “modify” the disease and avert damage.

Solanezumab, another anti-amyloid agent being developed by Lilly, also produced negative results in its first phase 3 clinical trials, which tested treatment for later stages of Alzheimer’s disease. However, results suggested the drug might be beneficial in subgroups who had very early Alzheimer’s. Now solanezumab is being retested at earlier disease stages in the large A4 trial, which is recruiting patients at dozens of sites in the United States and internationally (see our reports from September 2014 and June 2014). Reisa Sperling, MD, of Harvard, who received a 2010-14 BrightFocus grant for her amyloid imaging research, is helping to lead A4. (To learn more, watch this video.)

Despite fitful progress, anti-amyloid agents currently represent the nearest, best hope of taking Alzheimer’s treatment to a new level, where it’s possible to do more than achieve mild improvement in symptoms. These complexly designed biologically-active drugs have earned the title of potential “disease-modifying” agents because they’re believed capable of slowing down the disease and delaying onset of symptoms, including memory loss and cognitive decline.

All the evidence so far, including valuable knowledge gained from anti-amyloid trials that have failed, points to the likelihood that in order to stop Alzheimer’s, it has to be attacked very early in its 10- to 20-year course. That’s why disease-modifying agents are being targeted to the prodromal level and to very early, mild stages of Alzheimer’s disease.

Also, many experts now believe that Alzheimer’s disease doesn’t follow just one disease pattern, but make take several forms based on a patient’s genetic risk and other factors. That means anti-amyloid therapy may have to be customized to individual patients, and that more than one drug and/or approach may have to be used in combination. It will be important to have more than one plaque-fighting agent, as well as drugs attacking other aspects of the disease, at our disposal as clinical weapons.

Ebola raises profile of blood-based therapy


Convalescent plasma therapy is trialled to fight Ebola, but could also be used for new and emerging pathogens.

Survivors of Ebola carry antibodies that might be used to save the lives of those infected with the virus.

With no drugs available to treat Ebola, eyes are turning to a therapy that had largely been relegated to the history books: transfusing patients with blood plasma donated by survivors, which contains antibodies against the virus.

  • Clinical trials of convalescent plasma therapy (CPT) have started in the past few weeks in Liberia, and are due to begin soon in Guinea and Sierra Leone. If the therapy saves lives, the approach could quickly be scaled up.

Success would also raise awareness of CPT’s potential to treat other new and emerging infectious diseases for which there are no readily available effective drugs or vaccines, such as SARS, avian influenza and Middle East respiratory syndrome (MERS). “Clinical trials of convalescent plasma should be considered in other emerging infections,” says David Heymann, an infectious-disease researcher at the London School of Hygiene and Tropical Medicine, and chair of Public Health England.

Many scientists have long argued that CPT has been wrongly neglected, both as a therapy for emerging diseases and in preparation for future unknown threats. Today, the approach is gaining ground. Trials of convalescent plasma are beginning for the treatment of patients with MERS, which has infected 938 people and killed 343 of them since it was discovered in 2012. And an international protocol aimed at removing hurdles to quickly rolling out trials of convalescent plasma has recently been drafted.

Convalescent plasma was found to effectively treat diphtheria and tetanus at the end of the nineteenth century, and was widely used in the first half of the twentieth century to treat diseases such as measles, mumps and pneumonia. But it fell off the radar after the development of antibiotics, antiviral drugs and vaccines. (An exception was the adoption of CPT in Argentina for Argentine haemorrhagic fever after a successful controlled trial in the 1970s.)

When available, drugs and vaccines are usually a better option. They are easier to mass-produce and administer, and their quality and dosing can be better controlled. CPT is more complicated — it requires collecting survivors’ blood, screening it for pathogens and then organizing patient transfusion. And standardizing batches of plasma is difficult, because antibody levels in donated blood can vary widely.

But an epidemic or pandemic of a new pathogen turns that logic on its head. As in the case of the Ebola epidemic, there are typically no drugs or vaccines available, and developing these usually takes years. By contrast, “convalescent plasma is one of the few things you can get up and running quickly”, says Calum Semple, a paediatrician and clinical virologist at the University of Liverpool, UK, who is involved in the Guinea Ebola trial. Trials for Ebola and other emerging diseases “should have happened years ago”, he adds. He points out that the therapy is often considered old-fashioned and that there are neither big profits to be made nor cutting-edge-science interests at stake. “Convalescent plasma is not attractive to pharma, or the modern model of academia,” he says.

Results from the first safety and efficacy trials in West Africa are expected within weeks. If the therapy is effective, many of the thousands of Ebola survivors there will be potential donors, each capable of giving up to one litre of plasma every two weeks.

There is also growing evidence to support the broader testing of CPT. A 2006 review of 8 studies carried out during the 1918 flu pandemic1, and a review published last July of 32 studies on SARS or severe influenza2, both suggest that plasma can be an effective treatment. And a 2010 modelling study3 concluded that in a full-blown flu pandemic, the infrastructure of developed countries could probably harvest sufficient plasma from survivors for population-wide treatment of the ill. “It’s not the be-all and end-all, but it is certainly a potentially power­ful and effective tool to add to our armamentarium,” says Stephen Hoffman, a co-author of the 2006 review and chief executive of malaria-vaccine company Sanaria in Rockville, Maryland.

Even relatively poor countries often have a good-enough infrastructure for processing blood to use the therapy, says Heymann, who was part of the team that fought the first Ebola outbreak in the Demo­cratic Republic of the Congo in 1976. Plasma extraction can also be done in the field, he adds.

Adequate screening for pathogens in donated blood can be an issue in poorer countries. In the CPT Ebola trials, a chemical is being added to the donated blood. When the mixture is exposed to ultra­violet light, the compound irreversibly crosslinks the DNA and RNA of pathogens, preventing their replication.

It is also getting easier to test CPT more broadly. The International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC), a network of researchers based in Oxford, UK, was set up in 2011 to accelerate clinical research during outbreaks. It has now drafted a protocol for clinical trials of CPT that regulatory bodies can approve before an outbreak starts, allowing trials to be quickly carried out if necessary.

The protocol is being used in the Ebola trials and in clinical trials of CPT for MERS. These have begun in 20 patients in Saudi Arabia, and a larger trial of several hundred is planned over the next few months, says Yaseen Arabi, a physician and researcher at King Saud Bin Abdulaziz University for Health Sciences in Riyadh, who is coordinating the trials in collaboration with the World Health Organization and ISARIC. “Given the severity of illness and the lack of proven therapy, convalescent plasma has the potential of making a substantial difference,” says Arabi. “However, this needs to be tested.”

Amoxicillin Adverse Effects Underreported, Underrecognized


The adverse effects of amoxicillin appear to be underreported in clinical trials. In particular, treatment with amoxicillin-clavulanic acid commonly results in diarrhea, and treatment with amoxicillin-clavulanic acid or amoxicillin commonly results in candidiasis.

Malcom Gillies, PhD, from NPS Medicine Wise, Sydney, New South Wales, Australia, and colleagues published their systemic review and meta-analysis of randomized trials onlineNovember 17 in the Canadian Medical Association Journal. The review was intended to evaluate clinical studies and inform clinicians about harms from amoxicillin, thereby enabling physicians to make more informed decisions when prescribing this common antibiotic.

The team focused on 45 clinical trials (27 studying amoxicillin, 17 studying amoxicillin-clavulanic acid, and 1 studying both). Only 25 trials provided data that allowed the authors to evaluate harms. The authors conclude from this that adverse events were underreported in the medical publications.

The authors found that 10% of courses of treatment with amoxicillin were associated with diarrhea. They calculated an odds ratio for diarrhea of 3.30 (95% confidence interval, 2.23 – 4.87) for patients receiving amoxicillin-clavulanic acid compared with control patients. The odds ratio for candidiasis was significantly higher, at 7.77 (95% confidence interval, 2.23 – 27.11).

“Reported harms were fewer than we expected from clinical anecdotal experience and observationally derived data, which have primarily reported common harms as rashes (at rates of 5%–8% of those treated and even higher, up to 20%, among those with mononucleosis treated with amoxicillin) and gastrointestinal disturbance. Some standard textbooks do not report candidiasis. At least 1 case–control study found a relative risk of 7 for thrush after therapy with amoxicillin or amoxicillin–clavulanic acid,” they write.

The authors emphasize that their finding is likely not unique to amoxicillin. Genuine adverse events are often underreported in clinical trials.

The underreporting may be a result of poor monitoring, missing data, or lack of clear case definitions. Whatever the cause, the underreporting flows into systematic reviews and treatment guidelines.

In an accompanying editorial, Yoon Kong Loke, MBBS, MD, and Katharina Mattishent, MBBS, from the University of East Anglia in the United Kingdom, explain that the risk for bias toward the null should be explicitly assessed in systematic reviews. Such an approach will discourage the false sense of security that occurs when a drug is incorrectly declared safe or not significantly different from a comparator.

Dr Loke and Dr Mattishent also point out that absence of evidence of harm is not the same as evidence of absence of harm.

They suggest that quality assessment tools for adverse advents be incorporated into clinical trials to submit the claim of “no significant harm” to the same scrutiny that efficacy claims receive. Patients and physicians would also benefit from unrestricted access to complete trial data that include information on efficacy as well as adverse events.

Condom-less male birth control may be available as early as 2017


Studies suggest a new form of reversible male birth control is working in baboons, and clinical trials in humans are scheduled to start next year.

shutterstock_193541648

According to a recent statement from the Parsemus Foundation, a not-for-profit that focusses on developing low-cost medical solutions, a reversible, condomless male birth control option could be available as early as 2017.

The new birth control is known as Vasalgel, and is a non-hormonal polymer that blocks the vas deferens – the tube that’s cut during vasectomies, which transports sperms from the testes out of the penis. And trials in baboons suggest that it’ll be ready to be trialled in humans next year.

Six months ago Vasalgel was injected into three male baboons, who were then given unrestricted sexual access to 10 to 15 fertile female baboons each. Despite frequent mating, none of the female baboons have fallen pregnant, as journalist Samantha Allen reports for The Daily Beast.

The Parsemus Foundation is now going to flush the Vasalgel out of the baboons and test their fertility, to make sure that the procedure is definitely reversible. And another eight baboons are now beginning a new three- or six-month trial after being injected with Vasalgel.

“By the time the year ends, we will have a lot more information on the efficacy of Vasalgel – and, if all goes well, will be planning for clinical trials with humans to start next year,” the press release explains.

And, according to their FAQ page, the company hopes to see the treatment on the market by 2017 for less than the cost of a flat-screen TV.

Unlike most forms of female birth control, Vasalgel isn’t hormonal, and would only need to be injected once to block pregnancy for a long period of time. Basically, the polymer contraceptive is injected straight into the vas deferens, which it physically blocks up and stops any sperm getting through. A second injection flushes the polymer out when a man wants to reverse the procedure,Allen explains.

Of course, this contraceptive wouldn’t protect against sexually transmitted infections such as herpes and HIV, so condom use would still be recommended for many sexual interactions. But if all goes to plan, this will be an effective and much-needed additional option that couples can choose from when protecting against unwanted pregnancies. And more choice = more protection.

World-first clinical trials for better prosthetics based on antlers


Researchers in the UK are conducting the first clinical trials in the world where they are drilling prosthetics right into the bone, instead of moulded and strapped into place.

ITAP

Image: Royal National Orthopaedic Hospital

Right now, if a patient needs a prosthetic limb fitted, one will be made with a cup-shaped end that will be moulded to the base of their arm or leg and strapped on. It’s not elegant, or secure, or comfortable. But now a team of biomedical engineers at the Royal National Orthopaedic Hospital in London has just completed the first clinical trials of a new technique that has prosthetics drilled straight into the bone.

Named ITAP (Intraosseous Transcutaneous Amputation Prostheses), this technique grafts a little anchor directly onto the bone. The major problem with this technique though, is that this foreign body, which protrudes of the skin, has a high risk of getting infected. So the team looked at deer antlers, of all things, to find a solution.

Chris Higgins at Wired explains:

“Usually, any sustained breach of the skin barrier will allow foreign bodies through to invade. Antlers are specialised bone structures that transition from the skull into external features through the skin, but do not cause any adverse effects. The key to their organic survival is tiny, porous holes in the antler bone, allowing skin to grow into it and tightly infuse with the transdermal object, creating a barrier.”

With this in mind, the team at the hospital created a porous metal anchor that can be used to attach an array of specialised prosthetic limbs directly to the bone. The initial pain of having metal drilled into the bone will be offset by the increased comfort of the better-attached limb. According to Higgins, the 20 patients who took part in the clinical trial reported a better quality of life, some even describing it as “life-changing”.

Epigenetic Cancer Therapy Clears Phase I .


A new therapy designed to treat cancer by regulating gene expression has helped a handful of patients with blood malignancies in a preliminary clinical trial, according to pharmaceutical company OncoEthix. Today (April 7) at the American Association for Cancer Research (AACR) annual meeting in San Diego, California, the Lausanne, Switzerland-based firm presented unpublished data from a Phase I clinical trial of the drug, “OTX015,” a small-molecule inhibitor of the BET-bromodomain proteins BRD2, BRD3, and BRD4, which help to regulate gene expression. Seven of 38 patients for whom sufficient OTX015 trial data were available seemed to have benefited from the drug, OncoEthixannounced. Four of those seven patients have acute myelogenous leukemia (AML), while others enrolled in the trial have other hematological malignancies, including diffuse large B-cell lymphoma and multiple myeloma. One of the four AML patients experienced a complete response—meaning that his or her bone marrow and blood returned to normal—which is ongoing, the company said. The other three are still being treated with OTX015.

“To my knowledge, this is the first reported successful Phase I clinical trial with BET inhibitors targeting AML,” said Lin-Feng Chen, an associate professor of biochemistry at the University of Illinois, who was not involved in the work. “Although it is not completed yet, the results so far are very encouraging.”

“Everybody’s excited about bromodomain inhibition,” OncoEthix Chief Scientific Officer Esteban Cvitkovic said during an AACR press conference.

Pharma giant GlaxoSmithKline (GSK) and the Cambridge, Massacusetts-based firm Constellation Pharmaceuticals are among other drug companies with BET-bromodomain inhibitors in their pipelines. GSK’s I-BET762 is currently in a Phase I clinical trial.

Cvitkovic said that OTX015 has not yet shown cumulative toxicity. The firm is still working to determine the optimal dosing and schedule for the drug, administered as a monotherapy, he added.

“This trial . . . provides a great example for targeting epigenetic regulators for cancer therapy,” Chen wrote in an e-mail to The Scientist, adding that “the promising results from this trial will allow more clinical trials in the near future with BET inhibitors targeting other types of leukemia or cancers.”

Chen added that the study also paves the way for other investigational epigenetic cancer therapies. Targeting epigenetic machinery “provides a promising approach for treating drug resistance and clinical relapse and offers new option for combination therapy,” he said. “The major challenge is how to predict the treatment outcome. There is no clear biomarker to determine which patient would respond and benefit most from the therapy.”

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