Noxopharm Provides Update on Inaugural Clinical Study

noxopharmBelow, we are re-publishing with permission the press-release issued by Noxopharm on August 10, 2016

Noxopharm has completed putting in place the required logistics to enable it to conduct a clinical study of its lead pipeline drug candidate, NOX66, in Europe, commencing before the end of 2016.

The study is designed as a progressive Phase 1a/Phase 1b and prospective Phase 2a and is being conducted at two clinical sites in Tbilisi, Georgia. Georgia has been selected because of a combination of factors, including access to patients and speed of recruitment, availability of experienced investigators and good infrastructure for clinical research.

UK-based contract research organisation (CRO), Clinical Accelerator, has been appointed to manage the study. Clinical Accelerator specialises in clinical trials management in Central and Eastern Europe.

Data management and statistics will be conducted by Australian CRO, Datapharm Australia Pty Ltd.

A Sydney-based oncologist will act as senior Medical Monitor.

Overall management is in the hands of Dr Marinella Messina, Noxopharm Clinical Affairs Manager.

About the Phase 1a/1b/2a Study.

The Study is designed in 3 steps of NOX66 alone (Phase 1a) and various dosage combinations of NOX66 + carboplatin (Phase 1b) in a range of cancer types involving 15 patients, followed by a specific dosage combination of NOX66 + carboplatin in specific types of cancer (Phase 2a). Using this adaptive design, patients progress through the Phase 1a and Phase 1b arms providing they can tolerate the treatment and are deemed to be receiving a benefit from the treatment. Phase 2a is triggered by meaningful clinical responses in the Phase 1b arm and involves the immediate recruitment of an additional 20 patients involving a maximum of 2 specific tumour types.

All patients will have solid cancers that are unresponsive to standard cytotoxic chemotherapy. The primary objectives of the three progressive studies are (a) to determine the safety and tolerability of NOX66 alone and in combination with carboplatin, (b) to determine if NOX66 is able to reverse resistance to carboplatin in heavily drug-resistant cancers, and (c) to determine if NOX66 will allow the dosage of carboplatin to be lowered to a safer level without compromising its efficacy.

About NOX66

NOX66 is an innovative dosage formulation of idronoxil, a compound that down-regulates pro- survival mechanisms in cancer cells, including the cell’s ability to establish and maintain a range of drug-resistance mechanisms. The primary target of idronoxil is tumour-specific external NADH oxidase 2 (or ENOX2), the protein responsible for maintaining the transmembrane electron potential in the cancer cell’s plasma membrane. Loss of this potential inhibits the ability of the cancer cell to maintain a wide range of pro-survival mechanisms. NOX66 has been developed specifically to protect idronoxil from Phase 2 metabolism in the human body, thereby intended to increase the bio- availability of idronoxil to cancer cells. The primary clinical indications to be sought for NOX66 are (a) the ability to provide meaningful clinical response to frontline chemotherapies in cancers with high levels of drug resistance, and (b) the ability to lower the dosage of frontline chemotherapies to safer levels.

About Noxopharm

Noxopharm is an Australian drug development company with offices in Melbourne and Sydney. The Company has a primary focus on the development of drugs to address the problem of drug- resistance in cancer cells, the major hurdle facing improved survival prospects for cancer patients. NOX66 is the first pipeline product, with later generation drug candidates under development in an R&D program.

About Clinical Accelerator

Clinical Accelerator is an independent clinical trial management organisation operating principally in Central and Eastern Europe, Russia, Ukraine and CIS countries. The organisation offers a broad range of clinical trial services together with dedicated patient enrolment support to worldwide clients in the pharmaceutical, biotechnology, nutraceutical and medical device industries. Clinical Accelerator’s model of operation is designed to achieve cost-effective and time-efficient implementation of clinical studies for its clients with a firm focus on the quality of clinical trial data.

About Datapharm Australia

Datapharm Australia is Australia’s original full service contract research organization, celebrating 30 years in 2017. Services include: clinical trial management, set-up, monitoring, data management, statistical analysis and programming, medical writing, pharmacovigilance and auditing for Phase I to IV studies in over 35 therapeutic areas. Their electronic CRF system facilitates FDA-compliant data collection and smooth study conduct at sites globally.

* The study is conducted by Clinical Accelerator

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Brexit and Clinical Trials_Part 2

brexitWhat are the implications and consequences of the Brexit vote for the pharmaceutical and MedTech industries so close to the heart of most reading this piece? Many in these industries and in academic research establishments argued that a Brexit vote would be damaging for research and patient access and change the way drugs and medicines are tested and marketed; worryingly, two US companies intimated to the National Eczema Society that trials of new treatments would not take place in the UK in the event of Brexit.  Other campaigners, criticising ponderous bureaucratic nature the European Medicines Agency (EMA), have said that drugs could be made available more quickly if the UK votes to leave.

Whilst every EU member state has its own medical regulatory body (’Competent Authority’ – this being the MHRA in the UK) able to license new drugs, the European Medicines Agency (EMA) is currently a centralised body staffed and run by regulators from all EU member states providing marketing authorisation that is valid throughout all member states and countries in the European Economic Area (EEA i.e. EU plus Iceland, Liechtenstein and Norway).  Now, the EMA happens to be based in London, so the question is what happens given that the country with the EMA HQ is no longer to be a member?  It seems more than likely that the EMA will have to move its HQ out of London to an EU country. Apart from this obvious major upheaval, some in the pharmaceutical world argue that this will in itself reduce the importance of the UK in the eyes of the global drug companies.

If the UK decides to negotiate to stay in the EEA (a likely scenario?) there should not, in practice, be much difference to regulation. But if the UK stays out of the EEA, drug companies would need to go through a separate process with British regulators for new products without the benefit of a centralised European route.  However, UK drug and device companies will certainly want to market their products internationally, whatever happens to the infrastructure of the regulatory bodies and their internal procedures.  Thus it seems most logical that trials in the ‘independent’ UK must continue to run along the same guidelines as the rest of Europe. All procedures must still remain entirely compatible so that the EU could agree authorisation for marketing UK drugs and devices – one can argue that accepting this premise should mean no major changes in procedures and counter some expectations that not being an official part of EU-harmonisation might jeopardise the currently high degree of involvement in rare disease trials (the UK conducts around 40% such trials) as well as appeasing non-UK companies reluctant  to perform trials in the UK following Brexit.

There is also a move for even closer harmonisation within remaining EU states over the next few years to allow a single EU-central entry point for companies to apply for clinical trial authorisations (CTAs). Currently, of course each country still ‘competes’ to obtain their own CTA from Competent Authorities to local procedures.  Without care, this could distance the UK from EU regulations and trials conducted therein.

The Leave campaign argued that the existing EU Clinical Trials Directive has damaged medical research and innovation in the UK. For example, the UK Commons Science and Technology Committee said in a recent report: “Weaknesses in the 2001 Clinical Trials Directive significantly increased the administrative burden and cost of running academic clinical trials and saw a reduction in trials taking place in Europe.”  It did then acknowledge that the new regulations due to take effect in 2018 appeared to be an improvement [2].

There are legal aspects to consider: EU Directives governing medicinal products require the UK to implement relevant legislation into national law (done by reference to the European Communities Act of 1972 and through the implementation of the Human Medicines Regulation of 2012). The UK’s departure from the EU would mean these laws remain in place unless the UK government decided to change them.  Also, if the UK adopts national legislation that is significantly different to the new EU Regulation, this is likely to make the environment difficult for companies wanting to undertake trials in a number of countries that includes the UK.

Few would disagree that the result of the referendum vote is important for drug and MedTech companies and their products.  What of the reactions from some regulatory and official bodies?  Do these cast any light on future developments?  The MHRA, in their response, have said that they would work closely with the government to ‘consider the implications for the work of the Agency’ and to ‘continue to make a major contribution globally to improving public health through the effective regulation of medicines and medical devices, underpinned by science and research’ [3].   The statement from the Association of the British Pharmaceutical Industry (APBI) says that they ‘are committed to working closely with the government to agree what steps need to be taken to send a strong signal that the UK is open for business [4].

The European Federation of Pharmaceutical Industries & Associations (EFPIA) has said that it ‘shares the common goal of ensuring rapid access to innovative medicines for patients across Europe, as well developing a regulatory and policy environment that fosters innovation and supports the research and development of new medicines to meet the needs of patients, healthcare systems and society.  As an industry, over the coming months, we are committed to engaging with stakeholders both in Europe and in the UK to support these objectives’ [5].

Clearly nothing is clear among ‘the powers that be’ about the effects of all this and what will happen at this stage! There is still much conjecture, and given that the EFPIA has also rightly said that ‘The process of the UK leaving the European Union is likely to be long and complex. The pharmaceutical industry stands ready to work closely with governments and EU institutions to minimise its impact on patients and secure the future of medical innovation across Europe’, there is much to discuss and plans are yet to be put in place.  Trials will go on in Europe and, of course, in other territories not embroiled in the EU and its regulations. As for EU developments, it really is a case, to put it in medical terms, of ‘watchful waiting’…….

Brian Cary


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Brexit and Clinical Trials_Part 1


Well, the people of Britain have now spoken – albeit not that clearly given a 51.9%:48.1% split in the referendum voting figures. Nevertheless, it’s a democratic decision and now the word on almost everyone’s lips is “Brexit”. Despite a protest march and some other attempts to try and overturn the result or re-run the event (constitutionally problematic?), previously ‘pro-remain’ politicians in Britain now appear to be fully accepting the decision and will actively participate in what is set to be the long process of extricating the countries of the UK from central EU control.  Hopefully this ‘divorce’ will be an amicable one, retaining the good will and well established personal and trading relations with EU citizens and companies.

Looking at the statistics of the vote for a moment, which give an interesting insight into some demographics of the voting electorate, it appears that the leave result was swung somewhat by the over 60’s with younger people voting quite convincingly to remain – but being fewer in number the overall impact was dampened (perhaps apathy or indecision among the young led them not to vote?)   Age, aside, other demographics from the 382 separate voting areas indicated that ‘Leavers’ tended to be more prevalent in low income areas and (paradoxically?) from areas most economically dependent on the EU; whilst ‘Remainers’ tended more to be degree-educated, in jobs requiring a degree or have not travelled abroad recently (non-passport holders) but of course there was no clear-cut divide as these were statistical trends and I know many in the more elderly spectrum voting to remain [1].

All sorts of financial and social consequences of a vote to leave were mooted and, indeed, the expected dismay and turmoil on world financial markets followed the largely unexpected result immediately and although nerves (financial markets, at least, at the time of writing) seemed to have calmed somewhat, people in different industries and professions will be wondering what the future operating landscape for their businesses will look like.

In the second of these two pieces we shall consider some of the arguments for and against ‘Brexit’ for the Pharma and MedTech industries and whether there is any indication of what happens next.

Brian Cary


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Could Twitter Be a Recruitment Tool for Cancer Trials?

twitterAccording to Penn Medicine Researchers study’s, Twitter has the potential to promote patient recruitment into oncology clinical trials and increase the interest of patients [1].

Enrollment into clinical studies is crucial for the development of new treatment options for patients. It is also provides opportunities for those who are not responsive to the previous treatment or who cannot afford it. However, only about five percent of adult cancer patients participate in clinical studies, thus creating a problematic situation for the drug development environment.

According to statistics, approximately 15-20% of all trials never manage to enroll a single patient, 37% of all sites in a given trial fail to meet their enrolment targets. It is also worthy to keep in mind that nearly 30% of the time dedicated to clinical trials is spent on patient recruitment and enrolment [2]. To overcome this problem, companies are trying to reach their potential clinical trial participants via dedicated websites (Novartis), Facebook, Google, YouTube etc. [2].

Physicians from Abramson Cancer Center of the University of Pennsylvania analyzed a number of lung cancer tweets in the social media and found that a great number of posts were about clinical trials. Twitter users were particularly interested in immunotherapy. Surprisingly, only one tweet was used to help recruitment into a clinical study.

“Twitter provides a promising and novel avenue for exploring how cancer patients conceptualize and communicate about their health, and may have the potential to promote much-needed clinical trial recruitment.” said Mina S. Sedrak, MD, MS, a fellow member of the division of Hematology/Oncology at the Perelman School of Medicine at the University of Pennsylvania and first author of the study published online 3 March 2016 as a research letter titled “Cancer Communication in the Social Media Age” in JAMA Oncology.

Nowadays, there are numerous cancer care organizations and centers that use social media, including Twitter, for promotional and educational purposes. Penn Scientists tried to find out to what extent the information about clinical trails for cancer patients present on Twitter are useful.

In the pilot study, Sedrak and his coworkers analyzed a randomly chosen sample of 1,516 tweets out of a total of 15,346 that contained the phrase “lung cancer” from January 5 – 21, 2015, and assessed who read them.

More than half (56%) of the tweets were focused on psychological support and prevention topics. Nevertheless, clinical trials were the topic of almost 18% of analyzed tweets posted by patients, health professionals and other people, making these studies the second largest theme of social communication. Most of the clinical trial tweets (79%) were about immunotherapy studies, and 86% of them contained links directing readers to original websites and articles.

Authors were surprised to find that only one out of one and a half thousand analyzed tweets were linked to a patient enrollment website [1, 3]. According to them, although some more effort is needed to better assess social media involvement in cancer education, prevention and information, it is worthy to start using it as a tool for recruitment for the cancer clinical trials. On the other hand, social media patient enrollment will be the new challenge to institutional review boards with respect to non-coercive content and the assurance of patient’s privacy. New rules and policies may be needed in order to control the social media enrollment campaigns.

Sedrak sums up that “We need to learn more about the ecology of social media because it is clearly not consistently directing patients to the right places (…) social media may provide an infrastructure for cancer centers, researchers, and physicians to interact with the public in new and productive ways, including stimulating interest in new clinical trials with targeted messages that connect patients, caregivers, and families with trial enrollment websites. This potential remains largely untapped” [1].


  1. – assessed 23.06.2016
  2. – assessed 23.06.2016
  3. – assessed 23.06.2016
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We are celebrating an important milestone: – our tenth year of operation!

10yearsWe at Clinical Accelerator are happy to announce the celebration of 10 years successful provision of clinical research services to the biopharma, biotech and medtech industries.

Since our inception back in 2006 as a small provider of clinical trial management services in UK and several then emerging Eastern European countries, we have grown to be the larger organisation we are today. We now have many more established regions of operation and are present in 13 countries of Central and Eastern Europe (listed alphabetically these are: Armenia; Belarus; Estonia; Georgia; Hungary; Latvia; Lithuania; Moldova; Poland; Romania; Russian Federation; Serbia and Ukraine). We also have expanded our valued links with many more highly trained and experienced investigators to whom we are much indebted.

Let us also not forget the support and involvement of all the patients recruited at sites by these investigators, often facilitated by our own in-house patient enrolment support system.  We try to make our patients feel a valued part of the whole process rather than proverbial ‘guinea-pigs’ and their willingness to participate and adhere to sometimes quite challenging protocols (often travelling some distance to trial centres for assessment) always impresses us.

Our success is due, in no small measure, to our workforce. We are lucky to have such a dedicated team of clinical research professionals who have medical knowledge and practical experience in many regulatory and therapeutic areas and who work tirelessly to ensure timely delivery of all tasks contracted to us by our clients.  We find that the flat organisational hierarchy enjoyed by our qualified and competent team facilitates a good level of communication, flexibility, adaptability as well as a ‘can-do’ approach, which, we believe, is appreciated both by our team and our clients.

We are, of course, also most grateful and indebted to all our clients and collaborators over the last 10 years who have trusted us with their important projects. Being a part of the process in the development of your products has been most gratifying. The demands, challenges and feedback have encouraged us to evolve and develop new skills to meet varying and exacting needs.

A big ‘thank you’ to all our clients and collaborators for your support and kind words over this last decade.  We look forward to the next 10 years and beyond working with you and welcoming new clients and collaborators into the fold.

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Galmed Collaboration Announcement

Galmed Pharmaceuticals, Ltd. (PRNewsFoto/Galmed Pharmaceuticals, Ltd)

Clinical Accelerator are very pleased to announce collaboration with Galmed Pharmaceuticals Ltd. (NASDAQ: GLMD), on conducting a phase IIB clinical trial for the treatment of patients with overweight or obesity and who are pre diabetic or type II diabetic with the liver condition NASH (Non-Alcoholic Steatohepatitis) at seven sites in Georgia and Lithuania.

This trial is a multi-center randomized, double blind, placebo-controlled, dose-ranging Phase IIB study, which is evaluating the efficacy and safety of two doses of Galmed’s novel drug candidate , AramcholTM, in NASH overweight or obese patients who are pre-diabetic or already have type II diabetes [1].  The trial is already underway in other participating clinical sites in the USA, Israel, Europe and Latin America. Clinical Accelerator aims to add further impetus to recruitment at four sites in Georgia and three in Lithuania.

Eligible subjects are being enrolled into three treatments arms: Aramchol 400 and 600 mg tablets and placebo tablets in ratio 2:2:1.  Subject evaluations occur for 10 scheduled visits over one year. After completion of the treatment period, the subjects will be followed for an additional period of 13 weeks without study medication thus making 11 visits in all.

Aramchol , a conjugate of cholic acid and arachidic acid, is a first-in-class member of a novel family of synthetic Fatty-Acid / Bile-Acid Conjugates (FABACs)  and have been the subject of extensive research over the last 16 years by Galmed’s research team lead by the late Professor Tuvia Gilat.

Aramchol itself has already been shown in a phase IIA clinical study to statistically significantly reduce liver fat content as well as improve metabolic measures associated with fatty liver disease, having a simple once-daily oral dose with no severe adverse effects.

Clinical Accelerator is an independent clinical trial management organisation operating principally in Central and Eastern Europe, Russia, Ukraine and CIS countries.  The organisation offers a broad range of clinical trial services together with dedicated patient enrolment support to worldwide clients in the pharmaceutical, biotechnology, nutraceutical and medical device industries.

Clinical Accelerator always locates GCP-orientated sites with enthusiastic investigators who have the capability to conduct trials to high standards and challenging timelines at competitive rates of remuneration.  Moreover, patients in its areas of operation are usually very happy to participate in clinical trials and research studies, facilitating effective recruitment and retention.

We look forward to a very successful outcome for Galmed’s Phase IIB study and we are delighted to be one of their collaborators in the development of Aramchol, which is showing exciting potential for the treatment of the increasingly common condition of fatty liver disease.


  1. A Clinical Trial to Evaluate the Efficacy and Safety of Two Aramchol Doses Versus Placebo in Patients With NASH (Aramchol_005)



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Boosting patient recruitment and retention in clinical trials – fresh approaches?

Wpatiente hear much about ‘patient centricity’ and ‘empowering patients’ in clinical trials and research as well as everyday clinical practice.  This can be defined loosely as the process of designing a service or solution (e.g. a clinical trial) around the patient.  For clinical trials, this can mean engaging in a dialogue with potential patients or their families about the design of the trial itself including the protocol, trial schedule, number of interventions etc. so that it is considered acceptable and to try and ensure visits and data recording are made as easy as possible.  All this is to be achieved without compromising the scientific integrity and validity of the trial.  So although a good measure of pragmatism is called for one must still not lose sight of the trial’s aims and the necessary information required to achieve them.

The importance of being able to recruit sufficient patients as well as keep them ‘on study’ for as long as possible (one hopes for the full planned duration….) cannot be over-stated. Thus sponsors and researchers are always looking for ways to achieve this.  We know that it is not uncommon for trials to falter because the expected source of willing patients somehow dries up or, once recruited, they do not manage to stay the course.  This prolongs the timescale and compromises data.

In one such instance of attention to successful recruitment and retention, researchers at Nationwide Children’s Hospital (Columbus, Ohio USA) found ways to increase the number of people recruited and retained in one of their trials quite significantly. This was by seeking the advice of patients, families and other stakeholders in the design of a clinical trial investigating paediatric appendicitis.

The changes were made after the study had been initiated at the recommendation of a group of 20 individuals who are stakeholders on the research team, including (as appropriate to the paediatric study) children 7 to 17 years old, their families, physicians, nurses, patient educators and payers. The stakeholders provided input and advice to the researchers about all phases of the ongoing clinical trial in which the use of a tablet / smartphone app called Patient Activation Tool (PAT) is being investigated [1]. Changes were introduced to the patient information script, which initially simply said that they were ‘investigating a tool designed to improve decision-making about appendicitis treatments’ to a longer two-part message mentioning: i) aim to improve ‘the way in which the medical team communicates with families’ and ii) explanation to families that the study is ‘testing a tool designed to improve both physician-patient communication and promote shared decision-making about treatments’.  Simple changes in wording, but these were to yield impressive results.

To improve retention, the recommendation was to offer an online option via an e-mailed link for participants to complete follow-up questionnaires, to attain preferred times of contact and send out reminder letters about the follow-up assessments.

After these rather more patient/family-centred changes in information and simplifying provision of required data to reduce clinic visits were adopted into the study, rate of enrolment increased from 65 percent to 95 percent and the retention rate increased from 58 percent to 85 percent.  These are indeed encouraging statistics, which are reported in a communication to JAMA surgery [2].

Reportedly, the clinicians involved in the study were themselves surprised at the magnitude of the effect of the changes since recruiting patients for clinical trials, particularly those involving non-elective surgery, is often challenging with recruitment rates for paediatric clinical trials usually being under 50 percent. The study authors made the point that some people just don’t want to be part of research whilst others are afraid of the prospect, perhaps feeling like they are going to be ‘guinea pigs’ [3] . So it is important to approach them in such a way that they understand why it is important and why the results would be important to them or to others just like them.

Retaining those patients who do agree to enrol in a clinical trial is often difficult because it can be time-consuming for patients and their families to fill out the often lengthy and highly detailed follow-up questionnaires. The families of patients treated for conditions such as appendicitis are typically cured or feel better after treatment, so there may be little incentive to take the time to fill out the questionnaires.

The resulting jump in recruitment and retention rates from the study in question underscores the value of involving patients, families and other healthcare professionals when designing and performing clinical trials and making data reporting as patient-friendly as possible.

As we have seen in a previous post on this site [4] there are potential statistical implications in trying to deal with missing data in follow-up analyses when patients ‘drop out’ or do not adhere to the protocol properly – the more patients that are lost for follow-up, the further an analysis deviates from true ‘intention to treat’.  Patient-friendly approaches to data collection therefore aid statistical integrity and accuracy.

It is clear that many research approval Authorities now acknowledge the importance of ‘patient centricity’ and due regard for the role of patients and their families as well as other tangentially involved personnel when considering participation in clinical trials.  Indeed, for clinical trial or research approval applications some reviewing bodies specifically consider whether or not researchers have involved input from patients and stakeholders other than the researchers and sponsors themselves in the trial process.  For instance in the UK’s HRA (Ethics & Management) online application system one question to be addressed is:  In which aspects of the research process have you actively involved, or will you involve, patients, service users, and/or their carers, or members of the public?  Applicants have to tick which of the areas of research to which this applies: Design / Management / Undertaking / Analysis of results, and give details or ‘justify the absence of involvement’.  Although there may be instances where ‘justification’ of no such involvement may not be appropriate, this is a clear message that the authorities are now taking the matter seriously and directing researchers to consider these approaches.

The results of taking advice from a ‘stakeholder’ panel reported by the researchers at Nationwide Children’s Hospital in Ohio show that these considerations can produce dividends.  If you are a sponsor or researcher looking to place responsibility of designing, setting up or managing a clinical study, my advice would be to check with the research organisations being considered to see what ‘patient-centric’ solutions they offer in order to make your study run smoothly and to schedule.

Brian Cary

[1] Randomized Controlled Trial of a Patient Activation Tool in Pediatric Appendicitis (Antibiotics Alone vs. Appendectomy)

[2]  Minneci PC, et al., Improving Surgical Research by Involving Stakeholders. JAMA Surg. 2016 Feb 10. (doi: 10.1001/jamasurg.2015.4898).


[4] Statistical Controversies in Reporting of Clinical Trials Posted on March 14, 2016

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Statistical Controversies in Reporting of Clinical Trials

statisticsIn one of the recent issues of the Journal of the American College of Cardiology, Professor Stuart Pocock and colleagues discussed controversies in reporting clinical trial results.  Prof. Pocock is a well-known biostatistician from the Department of Medical Statistics at London School of Hygiene and Tropical Medicine who is a widely recognized expert in the field. In the article, the authors list multiplicity of data, composite endpoints, covariate adjustment, subgroups analysis, assessing of individual results, analysis of intention to treat (ITT) population and interpreting surprises as these issues that often are a real pain in the neck for statisticians.

One of the most important statistical issues in reporting of clinical trials is multiplicity of data, i.e. “repeated looks at a data set in different ways, until something statistically significant emerges” [5]. In other words, it seems really hard to validly select data from the numerous variables collected at baseline and during the follow-up, which should be included in major trial publications; just to ensure, that such report is fair to what it includes.

According to authors, the best way to avoid this problem is to have a predefined statistical analysis plan (SAP), that is fully signed off before database locking and study unblinding. Actually, SAP is a regulatory requirement, which must not be overlooked. Furthermore, it is critical to pre-define the primary endpoint (with definition of the endpoint itself), put particular focus should be on the time of follow-up and the precise statistical method for determining its point estimate, confidence interval (CI), and p value.

It is also good practice to have a pre-defined and limited set of secondary endpoints for treatment efficacy. Their results are shown alongside those of the primary endpoint. When the primary endpoint findings are inconclusive, claims of efficacy for any secondary endpoints are more doubtful, like in the PROactive (Prospective pioglitazone clinical trial in macrovascular events) trial [2]. Dormandy et al. put the emphasis on the main secondary endpoint with HR of 0.84 (95% CI: 0.72 to 0.98; p = 0.027) and ignored the lack of statistical significance for the primary endpoint (the HR was 0.90 (95% CI: 0.80 to 1.02; p = 0.095). Such practice from the regulatory point of view, is more than controversial, but as prof. Pocock says: “regulators need to recognize the statistical uncertainties” and interpret the results taking them into considerations.

Composite endpoints are the result of combining two or more outcomes into a single primary endpoint. Anyway, such combination may generate a risk of oversimplifying the evidence by highlighting the composite, without proper assessment of the contribution from each outcome separately. For example in the SYNTAX (Synergy between Percutaneous Coronary Intervention [PCI] with Taxus and Cardiac Surgery) trial of bypass surgery (CABG) versus the TAXUS drug-eluting stent (DES) [3, 4] composite primary endpoint comprising i.a. stroke, and repeat revascularization. It turned out, that more events appeared after DES, what suggests, that DES is inferior to CABG. Anyway, the main difference was in repeat revascularization (majority repeat PCIs). Then, there was a significant excess of strokes after CABG, even though there was no overall difference in the composite endpoint.

The next challenge in reporting clinical trial data is making a decision in terms of whether key results should be adjusted for baseline covariates, and if yes, which ones. Actually, this inconsistency is automatically managed in randomised trials, as randomisation ensures good balance across treatments for baseline variables, and hence, covariate adjustment usually makes little difference. Anyway, to avoid controversies, it is good practice to set-up an appropriate covariate analysis in the SAP. To gain it, first of all, one should specify a limited number of covariates known (on basis of prior knowledge) to have a significant impact on patient prognosis. Then, prepare SAP which contains the clear covariate-adjusted model which is to be fitted. Furthermore, one should avoid post-hoc variable selection- such choices may be used for enhancing the effect of the treatment. Finally- the covariate adjustment can be considered as primary analysis, if the choice of covariate is a generally accepted convention for a specific endpoint.

In many trials, recruited patients do not form a homogenous group. Hence, it may be important to check, if the effects of the treatment apply to the entire study population or depend only on particular baseline characteristic, i.e. age. Despite this fact, usually researchers face problems whilst interpreting the results of subgroup analyses. Trials usually lack power to reliably detect subgroup effects. Moreover, there may be too many subgroups, which one should control. Every additional subgroup analysis may increase the problems with statistical significance as every additional analysis impacts the overall p-value. Without losing in details, in case of several subgroup analysis you only can assure a significance level less than 5% comparison-wise with keeping the overall (study specific) significance level massively under 5% and making subgroup claims (i.e. p value does not reach 5%). To handle the statistical insignificance it is better to use statistical tests of interactions that examine the extent to which the observed difference for example in HRs across subgroups may be attributed to change in explanatory factors.

Even though there are no efficacy and safety differences between subgroups, there may be important differences between individuals. Therefore, one needs to determine the individuals’ risks and benefits in order to check if studied treatment is efficient and safe in each case. A good way to get appropriate results is by using multivariable logistic models to separately predict any patient’s risks. It aims to estimate on the absolute scale, how the trade-off between treatments differences in some particular parameters is patient specific.

One can also have some doubts about how to deal with missing data and non-adherence during follow-up analysis. Actually, it is almost impossible to have full follow-up data for every patient, because some of them withdraw from the study or are lost for follow-up. The more patients that are lost for follow-up, the further analysis deviates from true ITT; therefore, loss for follow-up should be minimalized. The easiest way to manage this is by improving treatment compliance and the second- even if subject drops out the study, his follow-up should be continued.

In the majority of time-to-event analysis there is a variation in the actual number of observed patients during the follow-up. However, if the patient is withdrawn from the earlier stage of the study, experiencing the primary endpoint cannot be assumed to occur at random (i.e. patient is likely to have higher risk of primary event, which is unrecorded). Consequently a relatively high percentage of early drop-outs might bias the estimation of the end-points. Neglecting this fact could lead to a biased treatment comparison.

The last, but not the least is interpreting unexpected findings which might be related to endpoints, subgroups, or treatment effects. Sometimes it is about an effect inconsistent with the overall treatment effect or an exaggerate effect, that exceeds prior expectations. Small studies can be the subject of this type or bias with a higher probability.

As Prof. Pocock concludes: “Nevertheless, controversies will continue to arise”, and he hopes that his paper “has provided a statistical insight that will help trialists to present and readers to acquire a balanced perspective.”


  1. Statistical Controversies in Reporting of Clinical Trials
  2. Dormandy JA, Charbonnel B, Eckland DJA, et al., for the PROactive Investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the ROactive Study (PROspective pioglitazone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005; 366: 1279–89.
  3. Serruys PW, Morice MC, Kappetein AP, et al., for the SYNTAX Investigators. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med 2009; 360:961–72.
  4. Mohr FW, Morice MC, Kappetein AP, et al. Coronary artery bypass graft surgery versus percutaneous coronary intervention in patients with three-vessel disease and left main coronary disease: 5-year follow-up of the randomised, clinical SYNTAX trial. Lancet 2013; 381:629–38.
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Replicor to present pre-clinical and updated clinical data on REP 2139-Ca based combination therapy in chronic HBV and HBV / HDV co-infection at APASL 2016

liverBelow, we are re-publishing with permission the press-release issued by Replicor on the 16th of February 2016

NEW YORK, February 16, 2016 – Replicor Inc., a privately held biopharmaceutical company targeting a cure for patients with chronic hepatitis B virus (HBV) and chronic HBV and hepatitis delta virus (HDV) co-infection, will present preclinical and updated clinical data on REP 2139-Ca based combination therapies in HBV infection and HBV / HDV co-infection at the 25th Annual Meeting of the Asia Pacific Association for the Study of the Liver to be held from February 20 -24, 2016 in Toyko, Japan. Three presentations on Replicor technology will be made during the meeting:

HBV RNA is emerging as a potential new marker of viremia in patients with HBV infection.  In patients with HBeAg positive HBV infection, treatment with REP 2139-Ca and immunotherapy (in the REP 102 protcol), not only leads to reduction /clearance of HBsAg and HBV DNA and the appearance of anti-HBs but also to reduction of HBV RNA as well.  The characterization of the HBV RNA response in the REP 102 protocol was done in collaboration with the lab of Dr. Hendrik Reesink at the Amsterdam Medical Center, and will be presented by Dr. Reesink in the Presidential Plenary Session on February 22nd.

An update on the clinical response data from HBV /HDV co-infected patients completing REP 2139-Ca / peg-interferon combination therapy and transitioning to peg-interferon monotherapy in the REP 301 protocol will be presented in an oral presentation on Feb 22nd (O-130).

A poster presentation on the effects of combined treatment with REP 2139-Ca and tenofovir disoproxil fumarate and entecavir on serum and liver virema in vivo will be presented on Feb 22nd (P-0329).

These pre-clinical and clinical studies continue to advance Replicor’s understanding of the antiviral effects of REP 2139-Ca based combination therapies and how these can be used to benefit patients with HBV infection or HBV / HDV co-infection.

For the APASL 2016 meeting and preliminary program:

About Replicor

Replicor is a privately held biopharmaceutical company with the most advanced animal and human clinical data in the development of the cure for HBV and HDV. The company is dedicated to accelerating the development of an effective treatment for patients with HBV and HBV/HDV infection. For further information about Replicor please visit our website at

* The study is conducted by Clinical Accelerator

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Quality Drivers in Clinical Trial Conduct – Part 2

Quality drivers 2This study aimed to illustrate how sponsors should measure quality of clinical trials and identify the various drivers of performance.  It was able to actually quantify the magnitude of the relationship between each of the drivers of performance and quality of conduct as well as measure quality directly. Routine trial management measures like ‘number of days to recruit’ and ‘number of data queries’ are simply measures of ‘time’ and ‘defect’, the authors point out, rather than a measure of quality itself – although they must surely be related to quality as performance drivers.

It is important to realise the implications of apparently ‘insignificant’ drivers of quality that were identified (e.g. the negative coefficients for ‘adherence’ and ‘monitoring’) since this is a bit misleading as the authors point out; for it means only that changing the level of the driver does not change quality and not that it is unimportant element of quality in a trial – they called such elements ‘hygiene drivers’ of quality that do not work to increase quality, but will ‘degrade’ quality if they are not present. In this respect, they discuss implications for risk-based monitoring (‘RBM’ – don’t we hear a lot about these days? No post on trials should be without a mention…). They say that using standard operational metrics to guide RBM could lead to a backward view of the trial and ‘gaming’ by the sites. With the obviously positive correlation between maintenance of good site relations and quality, there is complex relationship between attempts to maintain data integrity and quality of trial conduct.

All in all, the authors of this study maintain that the online (cloud-based) clinical trial questionnaire system they have developed is a statistically validated trial assessment platform that uses appropriate scientific measurements and can provide insights and data on quality that are not available from regular clinical trial management systems, which tend to be based on simple operational metrics.

Don’t fall into the ‘metrics trap’ they say. We should look beyond simple metrics to improve the quality of clinical trials and this seems to be sensible advice – despite the fact that it is from people who have a vested interest in a means of doing this…..

  1.…/Guidances/UCM269919.pdf (accessed 20/11/2015)
  2. Lawrence X. Yu, Pharmaceutical Quality by Design: Product and Process Development, Understanding, and Control. Pharmaceutical Research, April 2008, Volume 25, Issue 4, pp 781-791
  3. Howley, MJ and Malamis, P. Quality drivers in clinical trial conduct available at: (accessed 25/11/2015)
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