Why do rare disease clinical trials face greater challenges and what are some solutions?

Over 6,800 rare diseases such as Haemophilia, Tay Sach’s disease and Gaucher disease are affecting more than 25 million Americans. Still yet, there is limited understanding or knowledge of these debilitating, life threatening and progressive diseases. The Orphan Drug Act defines rare diseases as disorders affecting less than 200,000 people in the United States. Such a small patient population is the exact cause of problems and challenges in patient enrolment.

One requirement for the study of human diseases is an appropriate trial design. Randomization and control are considered essential if efficacy is to be attained and bias to be reduced, but for this a large sample must be acquired. However, due to scattered patient populations, variations among disease sub types and simply by necessity, clinical trials in rare diseases enrol small samples and still yet with difficulty.

This is partly due to the fact that the majority of rare diseases affect children and reduce lifespan. This leads to families being less likely to enrol their child into a study in which they may receive a placebo. Ethical issues may arise too as children are considered a ‘vulnerable’ population. In addition, problems occur if several studies are being carried out simultaneously as enrolment of a patient in one study may cause illegibility in another. As a result of enrolment challenges, it’s calculated that approximately 30% of phase III trials in rare diseases fail.

Clearly, rare diseases require an approach that is tailored to the study goal and specific indications. Two solution that are arguably vital are: in-home Clinical Trial Support and Patient Registries.

In-home Clinical Trial Support

Traditionally, patients are faced with the inconveniency of traveling to sites numerous times during the study. This puts strain on the patients’ budget and induces drop-outs. In-home Clinical Trial Support however takes into account the patients preferences and difficulties. The nurses travel to the patients’ home instead to carry out the clinical tests, PK sampling, drug infusion administration etc. This saves the patients major costs in regards to accommodation and reduces the number of visits to the sites making the concept of enrolment more appealing.

Patient Registries

With rare diseases it is often the case that sufficient data or information is unavailable. Patient registries help improve understanding and expand the knowledge base for companies developing treatments. Patient registries are global online data-repositories encompassing patients’ treatment-related health information which are created by several nations such as the U.S and Europe. They allow the development of communities which are able to share information regarding clinical trials which in turn increases the rate of patient recruitment, reduces enrolment delays, and allows better site planning as wider knowledge on the subject is made available.

The current status in regards to rare diseases is that we have a significant knowledge gap. In order to reduce this, continued collective efforts must be made to improve the clinical trial protocol design which will ultimately reduce time delays, hasten patient recruitment and most importantly, benefit those suffering from rare diseases.

References:

Augustine, Erika F., Heather R. Adams, and Jonathan W. Mink. “Clinical Trials in Rare Disease: Challenges and Opportunities.” Journal of child neurology28.9 (2013): 1142–1150. PMC. Web. 9 June 2017.

Khaleel, Samiya. “Rare Disease Patient Recruitment And Retention.” Clinical Leader. N.p., n.d. Web. 8 June 2017.

Leavy, Michelle, and Richard Gliklich. “Patient Registries and Rare Diseases.” Applied Clinical Trials. N.p., 2011. Web. 8 June 2017.

Stevenson, Danielle. “Clinical Trials for Rare Diseases – Finding and Keeping Patients.” BHD Foundation. N.p., n.d. Web. 8 June 2017.

Tirunagari, Sreedhar. “Rare Disease Clinical Trials‘Patient Recruitment Challenges.’” Global Health Trials. N.p., n.d. Web. 8 June 2017.

Anna Nikitina

Posted in Patient Enrolment, Rare Diseases | Leave a comment

Clinical Accelerator forms ClinAccel.Net

ca-net-logo

Clinical Accelerator forms ClinAccel.Net, a dedicated division focusing on expanding a network of partnering clinical research sites, and fast and efficient patient enrolment into clinical studies

Douglas, February 28, 2017 – Clinical Accelerator, a clinical contract research organization with operations in Central and Eastern Europe announced today the separation of its operations into two divisions. The clinical operations division will continue functioning as Clinical Accelerator, while a new dedicated division operating under the name ClinAccel.Net will be devoted to expanding a regional network of high enrolling investigators and supporting sites, and to designing and implementing proactive, regionally validated strategies of patient enrolment and retention.

Dr Nikolai Nikitin, CEO of Clinical Accelerator, stated, “Through this evolution, we will enable a deeper focus on the hugely important tasks of identifying and enrolling patients into clinical studies. The environment for patient enrolment is becoming ever more competitive throughout the world. It also affects the so-called emerging regions, such as Central and Eastern Europe where competition for patients and investigators has significantly intensified in the recent years.

Patient enrolment and retention support is now an important and well established service in the clinical trial industry and is offered by many international organizations. However, practical strategies often originate in locations with the highest competition for patients, such as the United States, and these strategies are not necessarily as effective in other parts of the world. We have been involved in patient enrolment and retention activities in Central and Eastern Europe for years and have developed and improved our customized, regionally validated models which work in our countries of operation. Through ClinAccel.Net, we plan to continue and further expand these services which we offer to international pharmaceutical and biotech companies, contract research organizations, and to regional clinical research sites.”

About Clinical Accelerator

Clinical Accelerator is an independent clinical trial management organization operating principally in Central and Eastern Europe, Russia, Ukraine and CIS countries. The organization 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 significant cost savings for its clients and to guarantee compact timelines for patient enrolment, with a firm focus on the quality of clinical trial data.

www.clinicalaccelerator.com

About ClinAccel.Net

CliniAccel.Net is a network of investigative and supporting clinical trial sites and a patient enrolment organization with a special focus on the region of Central and Eastern Europe. ClinAccel.Net helps pharmaceutical, biotech and medical technology companies as well as CROs to accelerate implementation of clinical trials through shorter start-up times and through faster patient enrolment. ClinAccel.Net improves efficiency and patient enrolling capacity of clinical research sites by optimizing their systems and procedures, and by employing a dedicated staff of patient enrolment managers who design and implement effective region-specific patient enrolment and retention strategies.

www.clinaccel.net

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Find FDA Documents by Name, Text and Other Keywords

searchOpenTrialsFDA works on making clinical trial data from the FDA (the US Food and Drug Administration) more easily accessible and searchable. Until now, this information has been hidden in the user-unfriendly Drug Approval Packages that the FDA publishes via its dataportal Drugs@FDA. These are often just images of pages, so you cannot even search for a text phrase in them. OpenTrialsFDA scrapes all the relevant data and documents from the FDA documents, runs Optical Character Recognition across all documents and links this information to other clinical trial data.

Explore the public beta version through a new user-friendly web interface at https://fda.opentrials.net.

László Szakács

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The EMA and Foreign Data_Part 2

emaPreviously we looked at data from the European Medicines Agency, which showed the increasing role since 2005 that some ‘Rest of the World’ nations were playing in enrolling patients in clinical trials supplying pivotal data for marketing authorisation applications (MAAs) of new medicines.  The rise in such trial activity in Middle East / Asia / Pacific region as well as the Commonwealth of Independent States (CIS) region (12 countries including Russia, Ukraine, Georgia etc.) in particular has been recognised by the EMA as being one of the major trends over the period [1].

One question then arises as to the view that the EMA take on the acceptability of such so called ‘foreign data’ studies and how they maintain quality.  It is also fair for pharmaceutical / Biotech companies, who are considering the placement of a clinical trial or study in a country not under the direct control of one of the EEA or FDA regulatory agencies to wonder whether the data produced in ‘ROW’ territories stands scrutiny and will be credible in the eyes of the global medical community.

The EMA state that regardless of where they are conducted, all clinical trials included in applications for MAA for human medicines in the European Economic Area must have been carried out in accordance with the requirements set out in Annex 1 of Directive 2001/83/EC. This means that:

a) clinical trials conducted within the EEA have to comply with European Union (EU) clinical-trial legislation (Directive 2001/20/EC) and that

b) those conducted outside the EEA have to comply with ethical principles equivalent to those set out in the EEA, including adhering to international good clinical practice (GCP) and the Declaration of Helsinki.  GCP is, after all, an international ethical and scientific quality standard for designing, recording and reporting clinical trials that involve the participation of human subjects. Guidelines for GCP were first introduced over 25 years ago by the International Conference on (now Council for) Harmonisation (ICH) with Europe, Japan, USA, Canada and Switzerland being current members However, they announced changes in October 2015, with reforms that mean that ICH is a truly global initiative, expanding beyond the current ICH members. More involvement from regulators around the world is welcomed and expected [2]

In the EEA itself, approximately 4,000 clinical trials are authorised each year. This equals approximately 8,000 clinical-trial applications, with each trial involving two Member States on average. Approximately 61% of clinical trials are sponsored by the pharmaceutical industry and 39% by non-commercial sponsors, mainly academia.

As reported in a previous post on this site [3] the European Commission adopted a new Clinical Trial Regulation (EU No 536/2014) on 16 April 2014, repealing Directive 2001/20/EC. The Regulation entered into force on 16 June 2014 but aimed to apply in the future after the IT infrastructure is place ‘no earlier than 28 May 2016’.  It has yet to be applied but will become the standard for European trials, which ‘outside’ countries will need to consider in terms of standards required even if not using the regulatory IT infrastructure involved in setting up and running. (For more information, see [4]).

The establishment and control of data quality in clinical trials by third parties as well as by those under direct EU regulation is underpinned by audit and inspection.

The European Medicines Agency closely monitors the data that applicants must include in their MAAs on the location of studies and the ethical standards applied for trials conducted outside the EU – the legislatory revisions of 2005 required this to reinforce the emphasis on ethical and GCP standards.

The number of GCP inspections – both routine and triggered – in third countries carried out by the inspectors of the national competent authorities of the EU / EEA Member States on behalf of the EU has increased by more than four times between 2006 and 2011.  Routine inspections are requested as part of the ongoing surveillance of the quality of studies received in MAAs, while triggered inspections are requested when the assessors identify specific concerns with the report and data on a trial which need a specific investigation by inspection.

A total of 357 sites were inspected at the request of the Agency’s Committee for Medicinal Products for Human Use (CHMP) between 1997 and 2011, with most inspections taking place since 2007. The pivotal trials submitted between 2005 and 2011 involved 70,291 investigator sites.

The country outside of the EU / EEA / EFTA area with the highest number of requested inspections was the United States (21.6%), followed by India (4.5%), Canada (4.5%), Russia (3.1%), Argentina (2.2%) and China (1.7%).

Since 1997 up to 2011 the number of inspections in the ROW region increased from 4 in 2006 to 19 and 26 in 2010 and 2011 respectively. The country outside of the EU/EEA /EFTA area with highest number of sites inspected was USA (21.57%) followed by Canada (4.48%), India (4.48%), Russia (3.08%) and Argentina (2.24%) [5].

In 2012, the European Medicines Agency published a reflection paper on ethical and GCP aspects of foreign clinical trials submitted in MAAs to the EU regulatory authorities. The paper outlined firm steps for international cooperation in the regulation of clinical trials, with a specific emphasis on initiatives for international cooperation and capacity-building to try and achieve a common approach to the oversight of trials. It also clarified and determined the practical steps by which EU regulators would gain assurance that ethical and GCP standards are applied to clinical trials for human medicines, both during the development and during the MAA phase [6].

It may be interesting to note in the EMA’s recruitment assessment (over the period 2005-2011) that the average number of patients per site in the ROW area was higher than in the two principal regions of EU/EEA/EFTA and North America (17 versus 13 and 10 patients respectively) [5]. This may be one reason that sponsors choose to place studies there: fewer sites to set up and ‘run’ for a planned number of subjects being more efficient and less costly.  Speed of initiation through streamlined processes with large numbers of trial-naive patients keen to participate are other reasons mentioned by sponsors along with overall costs without the large overheads.

The caveat in all this is that for ‘foreign’ studies whose results might be destined to be vetted by the EMA at any stage for whatever reason one should ensure regulatory, ethical and local site ‘GCP’ standards are maintained to EMA satisfaction.  That way the EMA is happy to accept such trial data, which stands scrutiny and engenders international credence.  Thus careful selection of trial area (country or countries) and investigator sites is important, whether this be directly by a sponsor (if capacity and local intelligence happens to allow) or by partnering with an experienced and well equipped trial management organisation delegated to oversee the study to whatever degree is preferred.

References:

  1. European Medicines Agency publishes report on patient recruitment and geographical location of clinical trials http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/04/news_detail_001758.jsp
  2. http://www.ich.org/about/organisational-changes.html
  3. https://clinicalaccelerator.com/2014/10/01/new-eu-trial-regulations-time-will-tell/
  4. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000629.jsp&mid=WC0b01ac05808768df
  5. Clinical trials submitted in marketing-authorisation applications to the European Medicines Agency: Overview of patient recruitment and the geographical location of investigator sites. Published 11 December 2013 (EMA/INS/GCP/676319/2012)
  6. Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities published 16 April 2012 EMA/121340/2011

 

Brian Cary

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The EMA and Foreign Data_Part 1

InEMA blog recent years we have seen an increase in the number of trials conducted for EU marketing authority applications (MAA) in areas other than what was considered to be in the two main European [European Union (EU) / European Economic Area (EEA) / European Free Trade Area (EFTA)] and North America [USA / Canada] territories.  In this first of two pieces on the European Medicines Agency (EMA) and its regard for ‘foreign data’ we shall look at the statistics on trial activity in the various territories and in the second piece, how the EMA regards foreign data and aims to maintains the quality.

Revisions to pharmaceutical legislation [Regulation (EC) No 726/2004 and Directive 2004/27/EC], which came into being back in 2005, reinforced the emphasis on the ethical standards required of clinical trials conducted in third countries to be included in MAAs submitted in the EU.  This raised some concern among regulators as well as in public debate about the level of ethical, scientific and organisational standards such as compliance with good clinical practice (GCP) and also about the available framework for the supervision and audit of these trials. The EMA issued guidance in 2006 providing an overview of key-procedural elements affected by the new legislation that could have an impact on applications or existing marketing authorisations [1].

The EMA groups all non-EU or North America regions into a third ‘Rest of the World’ (ROW) accounting category, itself comprising six zones: Africa; Middle East/Asia/Pacific; Australia/New Zealand; Commonwealth of Independent States (CIS i.e. 12 countries including Russia, Ukraine, Georgia etc. – incidentally, in which Clinical Accelerator principally operate along with some other non-EU countries); E Europe (Non-EU) and Central & South America.  It has been monitoring statistics on MAAs with trial activity for the various countries and has published reports on the data, which inform us of the changes in emphasis over the years since 2005.  The most current report available, published in December 2013 covers yearly data up to and including 2011; whilst not completely up to date it does reveal interesting information and trends [2].  Table 1 shows some information from 2005 and 2011 abstracted from this report to highlight changes in involvement of patients and number of sites over this period.

Between the years 2005 – 2011 almost 62% of the patients in trials submitted in marketing-MAAs to the EMA were recruited outside of the European Economic Area (EEA) and Switzerland, 34% being enrolled in Nth America and the remaining 28% in the other ‘ROW’ territories.  Notably, 9.4% of patients were recruited in the Middle East, Asia or the Pacific and another 9.4% in Central or South America.

Information on the geographical location of clinical trials allows the European medicines network to allocate resources for inspections where they are most needed, and to promote cooperation with local regulators to ensure efficient supervision of trials to expected standards.

Particular trends in the number of patients submitted in MAAs to the European Medicines Agency during the accounting period included:

–    Middle East / Asia / Pacific: an increase from 2.0% in 2005 to 12.8% in 2011;

–    CIS (Ukraine, Russia, Georgia etc.): an increase from 0.8% in 2005 to 7.5% in 2011.

In the EU (+ EEA / EFTA) itself, there was a decrease from 37.0% in 2005 to 31.2% in 2011. Within this region, the contribution of the 15 countries that were members of the EU before May 2004 plus Norway, Iceland and Liechtenstein fell from 32.1% to 19.4% over the observation period. The contribution of the countries that became Member States of the EU in 2004 and 2007 subsequently increased from 4.7% in 2005 to 11.7% in 2011, perhaps demonstrating one of the benefits of becoming EU members.

Meanwhile, from North America, there was a decrease in proportion of patients contributing to MAAs from 42.8% in 2005 to 31.5% in 2011.

Where there was an increase in number of patients involved in clinical trials, as one might expect, we also see a marked increase in number of sites becoming involved e.g. CIS countries from 72 to 807 sites (proportion of patients in all submissions rising from 1.3% to 6.2%).  Increases in trial activity can also be seen in the other ROW territories in terms of patient involvement but, as mentioned previously, the proportion (percentages) of the total are down as the ROW increases involvement.

Table 1 Statistics on enrolment and numbers of sites in 2005 and 2011*
  2005   2011
Territory Pts. (%) sites %   Pts. (%) sites %
EU/EEA/EFTA 32,090 37 1,974 35.2 44,590 31.2 4,548 35.2
Nth America 37,117 42.8 3,042 54.3 44,987 31.5 4,744 36.7
ROW 17,585 20.3 589 10.5 53,384 37.3 3,636 28.1
–  Africa 523 0.6 59 1.1 2,298 1.6 146 1.1
ME/Asia/Pacific 1,694 2.0 119 2.1 18,243 12.8 1,405 10.9
–  Australia/NZ 1,560 1.8 118 2.1 1,905 1.3 69 2.1
–  CIS 664 0.8 72 1.3 10,737 7.5 807 6.2
–  E Europe (Non-EU) 69 0.1 8 0.1 742 0.5 107 0.8
–  C / S America 13,075 15.1 213 3.8 19,459 36 902 7.0
(*figures abstracted from EMA publication 2013 [1])

What seems to have driven this emergence of trial activity particularly in areas such as Asia/Middle East and Central & Eastern Europe are somewhat simpler and pragmatic regulatory and approval systems coupled with an abundance of patients very willing to participate in trials with investigators also eager to be involved.  This has been considered, by some, to offer a more favourable and less costly trial environment than in the EU and associated states (and N America).

Understandably, this increased trial activity demonstrated in these figures – likely to be maintained or increased further since 2011 in new figures when published –  does lead one to ask about data quality and adherence to Good Clinical Practice in areas not directly regulated by the EMA or, indeed, the FDA.  In the second piece on this topic we shall look at the EMA’s regard to such ‘ROW’ trial data and how it ensures quality and acceptability for successful marketing authorisations.

References:

  1. Practical considerations on the impact of the new pharmaceutical legislation on Marketing Authorisation Applications via the Centralised Procedure and Centrally Authorised Medicinal Products for Human Use. EMEA/243280/2005
  2. Clinical trials submitted in marketing-authorisation applications to the European Medicines Agency: Overview of patient recruitment and the geographical location of investigator sites. Published 11 December 2013 (EMA/INS/GCP/676319/2012)

Brian Cary

 

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Regulatory Approval Received for VAL401 in Phase IIB Clinical Trial in Georgia

stamp

Below, we are re-publishing with permission the press-release issued by ValiRx on August 11, 2016

London, UK., 11 August 2016: ValiRx Plc (AIM: VAL), a life science company, which focuses on clinical stage cancer therapeutic development, taking proprietary & novel technology for precision medicines towards commercialisation and partnering, is pleased to provide an update on the clinical development of ValiSeek, the joint venture between ValiRx and Tangent Reprofiling Limited.

ValiSeek was formed to progress the novel cancer treatment drug, VAL401, towards Clinical Efficacy trials for the treatment of lung cancer and other oncology indications.

ValiSeek has received notification of acceptance by all required Regulatory Authorities in Georgia of the protocol and associated documentation for the Phase IIb Clinical Trial of VAL401 at the chosen site in Tbilisi. This acceptance allows ValiSeek to complete initiation of the clinical site at the Medulla Immunotherapy and Chemotherapy Clinic and allows Principle Investigator Dr Tsira Kortua to begin identifying patients to be recruited into screening. This screening process tests the patient suitability for induction into the trial protocol. All approvals have now been granted for this trial titled, “A Phase II study to assess the efficacy, safety and tolerability of VAL401 in the treatment of patients with locally advanced or metastatic Non-Small Cell Lung Cancer (NSCLC) after failure of at least one prior chemotherapeutic regimen”.

The approved protocol lists “Tumour progression-free survival” as the primary endpoint. This will record the length of time between patient screening and progression of the disease, providing a first indication of whether the treatment will be efficacious. Secondary endpoints include pharmacokinetic measurements; safety and tolerability of the drug; quality of life of the patients and overall survival, providing supporting data on efficacy and drug dosing parameters, which are key to aligning the programme with industry expectations. The protocol details the dosing and testing schedules to be carried out on each patient for six months treatment, with a maximum of twenty patients to be fully enrolled, with recruitment staggered over a number of months to ensure patient safety.

Clinical Accelerator, the UK-based clinical trial management organisation engaged by ValiSeek (as announced on 16 July 2015), will be building on their work of achieving this regulatory approval by coordinating the operational and logistical functions of the clinical trial.

This notification follows ValiSeek’s receipt of a positive opinion recommending approval of the trial protocol from the Ethics committee covering its clinical site in Tbilisi, as announced on 14 July 2016.

Dr Suzanne Dilly, CEO of ValiSeek Limited, commented: “It is very satisfying to have received confirmation from the regulatory experts that the trial has been correctly constructed and that the process of selecting patients for dosing can begin. After several years of preparation and pre-clinical testing, it is exciting to know that we can expect results to start arriving in the coming months.”

Dr Nik Nikitin, CEO of Clinical Accelerator, added: “I am pleased the set-up of this trial from one of our local Eastern European offices has proceeded smoothly and I know the site and principle investigator are keen to kick off the site initiation and to begin recruiting patients.” 

Dr Satu Vainikka, CEO of ValiRx Plc, added: “We at ValiRx are absolutely thrilled to get this approval for our VAL401 treatment to go to late stage clinical trial for this desperate unmet medical need”.

This announcement contains inside information for the purposes of Article 7 of EU Regulation 596/2014.

Notes for Editors

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 significant cost savings for its clients and to guarantee compact timelines for patient enrolment with a firm focus on the quality of clinical trial data.

About ValiSeek 

ValiSeek Limited (“ValiSeek”) is a joint venture (“JV”) company between ValiRx Plc and Tangent Reprofiling Limited, part of the SEEK Group. ValiSeek was formed to progress the drug VAL401 through its remaining preclinical development and towards Phase II trials for the treatment of lung cancer and other oncology indications.

About SEEK

Founded in 2004, SEEK (previously known as PepTcell) is privately-owned and funded, with headquarters in London, UK. SEEK brings safe and low costs medicines to the patients as quickly as possible. It does this by modifying existing medicines to improve their efficacy within current label, dose and regime, by changing the indication but keeping the dose and dosing regime the same or by creating a new medicine when the previous options are unavailable.

Additional information about SEEK is available on the Company’s website located at www.seekacure.com.

ValiRx Plc

ValiRx is a biotechnology oncology focussed company specialising in developing novel treatments for cancer and associated biomarkers. It aims to make a significant contribution in “precision” medicine and science, namely to engineer a breakthrough into human health and well-being, through the early detection of cancer and its therapeutic intervention.

The Company’s business model focuses on out-licensing therapeutic candidates early in the development process. By aiming for early-stage value creation, the company reduces risk considerably while increasing the potential for realising value. The group is already in licensing discussions with major players in the oncology field.

ValiRx’s two classes of drugs in development, which each have the potential for meeting hitherto unmet medical needs by existing methods, have worldwide patent filings and agreed commercial rights. They originate or derive from Word class institutions, such as Cancer Research UK and Imperial College.

Until recently, cancer treatments relied on non-specific agents, such as chemotherapy. With the development of target-based agents, primed to attack cancer cells only, less toxic and more effective treatments are now possible. New drugs in this group—such as those in ValiRx’s pipeline—promise to greatly improve outcomes for cancer patients.

The Company listed on the Alternative Investment Market (“AIM”) of the London Stock Exchange in October 2006 and trades under the ticker symbol: VAL.

* The study is conducted by Clinical Accelerator

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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

References

  1. https://next.ft.com/content/1ce1a720-ce94-3c32-a689-8d2356388a1f
  2. http://www.publications.parliament.uk/pa/cm201617/cmselect/cmsctech/158/15807.htm
  3. https://www.gov.uk/government/news/medicines-and-healthcare-products-regulatory-agency-statement-on-the-outcome-of-the-eu-referendum
  4. http://www.abpi.org.uk/media-centre/newsreleases/2016/Pages/UK-must-send-strong-signal-it-is-open-for-business.aspx
  5. http://www.efpia.eu
Posted in European Union | Leave a comment

Brexit and Clinical Trials_Part 1

brexit

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

References

  1. https://next.ft.com/content/1ce1a720-ce94-3c32-a689-8d2356388a1f
Posted in European Union, Uncategorized | Leave a comment

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].

References

  1. http://www.uphs.upenn.edu/news/News_Releases/2016/03/sedrak/ – assessed 23.06.2016
  2. http://pharmaphorum.com/views-and-analysis/using-social-media-for-clinical-trial-recruitment/ – assessed 23.06.2016
  3. http://www.symplur.com/blog/twitter-future-clinical-trial-recruitment/ – assessed 23.06.2016
Posted in Patient Enrolment, Social Media | Leave a comment