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Giuliana Miglierini

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UK: An app to measure glucose without the need of blood samples

Giuliana Miglierini
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UK: An app to measure glucose without the need of blood samples

Artificial intelligence is no more just a conceptual idea, as the first examples of its applications are entering the real world carrying with them a disruptive potential that might deeply change many habits including healthcare management. Just think to diabetic patients, who need to extract two-three time a day a drop of blood from their fingers to measure glucose concentration (a total of up to 3,000 times a year stabbing their fingers): how better would be their quality of life if it would be possible to avoid such an annoying procedure? The first glucose-meters for home use appeared some 40 years ago, and today it is time for a new revolution, as the first app for mobile devices claimed to be able to monitor blood sugar levels and cardiovascular indicators – such as heart rate and blood pressure – without invasive measurements is under clinical development in the UK.

How it works

Nothing easier than just place a fingertip over the camera lens of the smartphone: a series of images are then taken which allows the app to accurately figure out information about the user’s blood flow. The images are then sent to the cloud for analysis; the data so obtained are used to provide an accurate account of vital parameters, including blood sugar levels.

The analytical method developed by Bioepic, a start-up company based in Hereford and founded in 2016 by Dominic Wood, was validated in comparison to traditional invasive procedures through pre-clinical trials. The Epic Health app also provides personalised advice and alert, based on advanced analytics to examine current and historical data and forecast immediate trends of blood glucose levels.“We have now validated our technology with private studies and Proof of Concept (POC) trials” said Dominic Wood, CEO of Epic Health.

The first part of a pre-clinical study considered a total of 79 subjects with diagnosed type 2 diabetes, including undiagnosed “borderline” type 2, and healthy glucose levels took part in the data collection study. According to the company, obtained data showed that 90.58% pairs of results were in the ‘no risk’ zone and 8.88% of pairs were in the ‘slight lower’ area giving a combined 99.4% safe clinical error result.

A new clinical trial has been announced by the company, which will include 700 Britons, 700 Americans and 700 Chinese citizens in order to consider ethnic diversity. “Part 1 of our pre-clinical study covers healthy, borderline type 2 and diagnosed type 2 diabetic subjects. Part 2 of the study, to be reported in the next two months, will cover diagnosed type1diabetic subjects. We then move on to a full clinical trial. The main difference between the study reported here, and the full clinical trial, is that we will be comparing the clinical accuracy of our app with serum blood values rather than blood taken from the dermal layer of the skin, which often is not the same thing”, explained Dr Richard Wood, Chairman of Epic Health.

A better quality of life for diabetic patients

“My father lost his battle to diabetes two years ago and I know he had terrible trouble in managing his blood tests. This app, if around then, would have made his life so much easier to keep on top of his therapy”, commented Non-Executive Director Prof. Luigi G Martini, Fellow of the Royal Pharmaceutical Society and Professor in Pharmaceutical Innovation.

There are more than 2.3 billion people at risk of developing adult-onset diabetes according to the World Health Organisation. The availability of non-invasive procedures to measure glycaemia may have a deep impact not only on the management of diabetes, but also on the possibility to closely monitor pre-diabetic conditions, thus helping in the prevention of the disease, as people would be encouraged to understand how certain foods affect their body. The great part of the at-risk population has never checked, for example, insulin resistance or blood glucose because of cost constraints or lack of awareness.

The Epic Health app is just one of the many examples of AI technologies under development for a better management of diabetes. Wearable devices, for example, can be used to monitor the heart functioning during exercise, thus preventing issues that are often related to cardiac arrhythmias in insulin-resistant people at risk of type 2 diabetes. Smart patches able to continuously monitor glucose levels and deliver an as-necessary insulin dose are also under development.  Intelligent contact lenses are another possibility under study to continuously track glucose level; a project jointly started by Google and Novartis, but which is suffering technical issues that have apparently blocked the development, as reported by the press.

Exome sequencing of genetic data to speed up R&D

Giuliana Miglierini
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Exome sequencing of genetic data to speed up R&D

The new era of personalised medicine is already here, as the first CAR-T therapies and other types of genetic interventions are undergoing clinical testing. But a final step is still required to extract a better predictive value from the genetic data to be used in R&D activities to optimise drug development. A clear understanding of the link between the biological target of a drug and human diseases is a fundamental pre-requisite to develop new strategies of drug development able to improve the ratio of successful drug candidates that reach the market. An estimated 90 percent of candidate medicines entering clinical trials currently fail to demonstrate the necessary efficacy and safety profile, resulting in a high impact on R&D costs sustained by pharmaceutical companies. Genetic evidence is playing an increasing role in the pre-clinical validation of drug targets, even at the level of individual patients, thanks to the availability of a personalised pool of biomarkers to be used to diagnose the disease and monitor its evolution.

A new consortium to speed up research

Drug target identification, genetically-validated clinical indications and genomic markers for pharmacogenetic application are just some examples of the possible applications of genetic big data analysis. A type of information that is central to the new pre-competitive consortium that will fund the exome sequencing of the biological samples obtained from the half million volunteers adhering to the UK Biobank.

The consortium holds together six major pharmaceutical companies – Regeneron (the leading company), AbbVie, Alnylam Pharmaceuticals, AstraZeneca, Biogen and Pfizer. The project represents a $10 million effort for each of the adhering companies, with the goal to make available exom sequencing data by the end of 2019, together with associated de-identified medical and health records of the volunteers. It shall thus be possible to extract information from big data analysis to be used to speed up R&D activities. According to Regeneron, consortium members will have a limited period of exclusive access to the exome sequencing data and findings before they will be openly made available to other researchers by the end of 2020.

The next step of the project, said the company, will include sequencing of the entire genome of UK Biobank participants: nevertheless, an activity that will not be completed for several years after the closure of the current exome sequencing project.

Linking human genetic variations to human biology and disease

A first step of the project was run in 2017 with the support of Regeneron and GSK, when an initial pool of 50,000 people adhering to the UK Biobank was sequenced; the complete sequencing of all samples was then expected to terminate in 2022. The timeline has now greatly improved thanks to the formation of the consortium; sequencing of the samples will continue to be performed at the Regeneron Genetics Center (RGC) facility. The so obtained genetic data will be paired with the detailed health information stored by the UK Biobank, among which are brain, heart and body imaging as well as behavioural and psychological information on participants (all under anonymous form). It will thus become possible to link the genetic variations identified by data analysis to human biology and disease.

“With mounting national and global health concerns due to widespread increases in obesity-related diseases like diabetes, and age-related diseases such as dementia, together with the ongoing threats of cardiovascular disease, cancer and infectious agents, it is a great statement that so many leading Life Sciences companies are willing to put aside their individual differences and come together to bring this unprecedented, pre-competitive ‘big data’ resource to the world. We all hope and believe this will greatly accelerate our collective efforts to make a profound impact on human health,” said George D. Yancopoulos, President and Chief Scientific Officer of Regeneron.

The main partners of the project

The UK Biobank already completed a genotyping project on its 500,000 samples, those results were published in mid-2017. Genotyping offers a lower precision level of the extracted genetic information, as it just measures specific “letters” in DNA at select locations across the genome. Exome sequencing goes into far more detail, as it records every letter in the DNA of the exomes, i.e. the 1-2 percent of the genome coding for all known proteins. Expressed proteins are believed to be more relevant for therapeutic development and understanding of inherited disease and they represent a common target for drug development.

The UK Biobank is a public institution founded by the Wellcome Trust and the UK Medical Research Council and it represents the most comprehensive resource of its kind in the world. Approximately half a million volunteers, both healthy and ill people, have provided the Biobank with information about their health, well-being and lifestyle, as well as blood and other biological samples for long-term storage and analysis. The project extends further, as the volunteers are followed for many years for the evolution of their health conditions. The data stored by the UK Biobank are anonymised and can be accessed by scientists for research intended to improve the prevention and treatment of a wide range of common disorders.

The Regeneron Genetics Center’s fully integrated genomics programme spans early gene and target discovery, functional genomics and genetics-guided drug development. The role played by RGC in the new pre-competitive consortium is just the last of its more than 60 collaborations with leading human genetics researchers and biobanks around the world. The Center has already sequenced samples from more than 250,000 appropriately-consented individuals, using its fully-automated sample preparation and data processing equipment, cutting-edge cloud-based informatics and large-scale analytical capabilities.

ICMRA: towards global standards for track-and-trace systems

Giuliana Miglierini
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ICMRA: towards global standards for track-and-trace systems

The International Coalition of Medicines Regulatory Authorities (ICMRA) adopted on 25th October 2017 the new “Recommendations on alignment of existing and planned track and trace (T&T) systems to allow for interoperability”.

Interoperability is a central issue to reach an efficient operational flow along the entire life cycle of medicinal products. From the active ingredient entering the production plant to the distribution of the finished dosage form to the single patient, each step of the process has to be tracked and registered in order to ensure quality, reduce risks and achieve compliance. Interoperability is defined as “the ability of T&T systems to exchange information and make use of the information received from other systems”. While track-and-trace systems are already requested from the regulatory point of view at the international level and as a mean to fight counterfeiting of medicines, there is still lack of uniform standards to develop them.

A still fragmented framework

The fragmentation is not limited to different systems put in place by different countries: it might occur also at the national level, where different authorities may implement different T&T systems. The result is the impossibility, or a lower capacity, to rapidly exchange relevant regulatory information among different authorities, something that might undermine the integrity of the supply chain and the protection of patient safety.

ICMRA recommends establishing “a common language among the supply chain regulatory and industry actors” in order to directly support “the identification and management of risks associated with counterfeit or substandard health products” and improve pharmacovigilance. The Coalition identified supply-chain integrity as a priority in November 2015. The Annex to the Recommendations provides further details on the current implementation of T&T systems for medicines at the global level.

Issues and targets to achieve interoperability

The establishment of a minimal global set of technical features or standards should be the fundamental target to be pursued to achieve alignment of T&T systems and interoperability. A further issue highlighted by the document are the different rules governing confidentiality of business information and legal ownership of information, which may limit interoperability and transparency to be shared among different jurisdictions via T&T systems. ICMRA focused on the possible exchange of information only in cases where there is a serious threat to public health.

The Recommendations also discuss different types of T&T systems, i.e. full systems (which allow full traceability of the product transactions from beginning to end of its supply-chain, including the agents in the middle e.g. distributors), end-to-end systems (systems which allow verification of the product status only at the beginning and at the end of its supply-chain) and systems in-between (partial verification between the beginning and the end of its supply-chain, in addition to end-to-end).

Costs of development represent another barrier to implement T&T systems in some jurisdictions. Last, but no less important, a political consensus is needed to reach interoperability between T&T systems.

How to achieve the benefits of interoperability

The final goal is the traceability of products and batches throughout the global supply-chain, in order to minimise patients’ exposure to risks derived from defective products. Interoperable T&T systems would allow to track (in real time) movements of the product across different jurisdictions, something essential to identify the origin of quality and safety issues, to support pharmacovigilance or scrutiny of falsified incidents, and to inform mitigation measures. The management of drugs shortages might also benefit from interoperability.

Among the suggestions made by ICMRA is the standardization of the information present on packs of medicinal products. An International Common Product Identifier (independent from the name of the product in the different regions), the International Batch Number and the expiry date are the features that should always be present, while other information (e.g. serial numbers, reimbursement numbers etc.) can be included according to national/regional requirements. The Coalition suggests the use of ISO Identification of Medicinal Products (IDMP) standards to uniformly build the relevant information.

Data coding standards should also be common to different jurisdictions, and the same kind of data carrier should be used throughout the interoperable systems. An example of an economic solution suggested by the Recommendations to achieve this is the use of 2D data-matrix code.

The next steps

The needed consensus among ICMRA members, states the document, should be reached using the instrument of technical international fora to discuss common standards for T&T systems and identify technical solutions to enable interoperability. The Recommendations also suggest to better evaluating possible synergies with other related topics, such as big data and pharmacovigilance or the adoption of IDMP standards. The introduction of new technologies should be only a target for the future, but it is now essential to focus on already existing systems. To proceed towards these goals, ICMRA will identify a technical expert body that should address how to implement the principles described by the Recommendations.

What is going on in neurosciences?

Giuliana Miglierini
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What is going on in neurosciences?

It is indeed not a good time for R&D in neurosciences, as Pfizer is just the latest case of major pharmaceutical companies experiencing issues in the development of their pipelines targeted to Alzheimer’s and Parkinson’s diseases. A positive signal for the sector is represented by Bill Gates entering dementia research. There is still a lack of therapeutic interventions able to address the increasing numbers of neurodegenerative diseases. The global costs to treat Alzheimer’s disease amounted in 2015 to $818 billion, according to Nature, with an expectation of 70 million people suffering the disease in 2030.

Pfizer leaves the challenge

Pfizer’s decision to stop research on Alzheimer’s and Parkinson’s disease came at the beginning of January 2018, when the company announced the elimination of 300 positions from the neuroscience discovery and early development programmes at the global level (see the report by the Wall Street Journal). According to the company, the resulting money will be re-allocated to stronger areas of expertise. Pfizer was among the industrial founders in 2015 – together with GSK and Eli Lilly – of the venture capital fund Dementia Discovery Fund. According to the company, a new venture fund will be launched to invest in neuroscience research projects. Pfizer also says it will continue to support the development programmes of tanezumab to treat late-stage pain, of pregabalin (Lyrica) for fibromyalgia and will pursue research into neurological drugs for rare diseases. A first failure in Alzheimer’s research came from the bapineuzumab project, jointly developed by Pfizer and Johnson & Johnson and closed in 2012 due to lack of results in patients with mild to moderate Alzheimer’s disease.

“The research and development pathway for a new drug is a long and costly challenge, that might potentially undergo a very high risk of failure – wrote the president of the Italian Medicines Agency (AIFA), Mario Melazzini, in a commentary on Pfizer’s decision -. Nevertheless, with reference to the goals posed by important challenges and the unavoidable hiccups, research almost always finds new impetus to critically revise its models and to identify new and more efficient strategies”. According to Melazzini, there are more than 190 clinical studies ongoing at the global level on 100 different active ingredients, 47 of which are late phase studies.

The other main failures

In December 2016 Eli Lilly published the detailed results of its phase 3 trial with the investigational drug solanezumab in people with mild dementia due to Alzheimer’s disease (AD); the drug did not meet the primary endpoint of the trial and the development programme was thus stopped.

Axovant Sciences also abandoned research on Alzheimer and Parkinson after the failure of its investigational drug intepirdine to meet primary efficacy endpoints in two Phase 2 studies. The company also reported the misinterpretation of clinical results on another investigational drug, nelotanserin, during the pilot Phase 2 Visual Hallucination study. According to Axovant, a larger confirmatory nelotanserin study might be discussed in future with the FDA, focused on patients with dementia with Lewy bodies (DLB) with motor function deficits; the candidate drug might be further evaluated also for psychotic symptoms in DLB and Parkinson’s disease dementia (PDD) patients in future clinical studies.

The results obtained with Lundbeck’s candidate idalopirdine in three different randomized clinical trials – a total of 2,525 patients with Alzheimer’s disease treated with cholinesterase inhibitors – demonstrated that the added use of idalopirdine compared with placebo did not decrease cognitive loss over 24 weeks. The findings published in JAMA do not support the use of idalopirdine the treatment of Alzheimer’s disease.

Others are investing

The Alzheimer’s Prevention Initiative (API) Generation Study 2 is a new project jointly launched in November 2017 by Amgen and Novartis to test BACE1 inhibitor CNP520 for its ability to prevent or delay the onset of Alzheimer’s disease symptoms in a high-risk population. The programme consists of two pivotal Phase 2/3 studies; the drug candidate targets BACE1, an enzyme that plays an important role in the production of the protein amyloid β, which is characteristic to Alzheimer’s disease. The study is expected to enrol – across 180 clinical centres in 20 different countries – approximately 2,000 cognitively healthy participants at high risk of developing Alzheimer’s based on their age (60-75) and who carry either two copies of the apolipoprotein E (APOE) 4 gene or one copy of the gene with evidence of elevated brain amyloid.

But pharmaceutical companies are not the only ones to invest in research on neurodegenerative diseases: billionaire philanthropist Bill Gates invested $ 50 million last November in the Dementia Discovery Fund.  Personal reasons are at the base of his decision, as his 92-year-old father suffers with Alzheimer’s disease. “I really believe that if we orchestrate the right resources, it’s solvable,” told Gates in an interview published on the Fund website. The main target of this investment is new, unconventional research. Gates also invested $ 50 million to fund a national patient registry in order to speed up recruitment for clinical trials, as well as a ground-breaking international database for research that will help scientists share data and stimulate collaboration. “By looking at this data, we can start to understand, whether there are multiple syndromes here that are slightly different? Is it different in different races; is it different from men than women?” said Gates.

A new biotech facility for Ferring

Giuliana Miglierini
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A new biotech facility for Ferring

Ferring Pharmaceuticals is going to invest approx. CHF 30 million to built its new Ferring Biotech Centre, located at the company’s existing headquarters and manufacturing site in Saint-Prex, Switzerland.
The operation intends to improve the company’s capabilities in biologics over the next three years; the new Centre will incorporate the already existing discovery and development capabilities for monoclonal antibodies as well as biologics manufacturing capabilities.
According to the company, the new Ferring Biotech Centre will host the discovery, development and manufacture of new biologics, as well as the manufacturing of the active pharmaceutical ingredient follitropin delta, the company’s latest fertility treatment launched on the market.

 

“Ferring is committed to investing in innovative technology platforms to create new solutions for patients in our core areas of reproductive medicine and women’s health, gastroenterology and urology,” said Michel Pettigrew, President of the Executive Board and Chief Operating Officer, Ferring Pharmaceuticals. According to Pettigrew, this significant investment in state-of-the art manufacturing and development technologies fits the strategy to address unmet patient needs in core areas of the company, and will also open up additional opportunities.

A partnership for ultra-rare disease APECED/APS-1

Giuliana Miglierini
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A partnership for ultra-rare disease APECED/APS-1

It has been signed between the German biotech company ImmunoQure – founded in 2011 by a consortium of scientists, biotech entrepreneurs, and APECED/APS1 patients – and the pharmaceutical company Servier the new, worldwide, exclusive partnership for the advancement of ImmunoQure’s therapeutic human Interferon-alpha autoantibody through preclinical development up to the clinical phase, that will be directly managed by Servier.
The clinical target are diseases driven by elevated levels of interferon-alpha, i.e. systemic lupus erythemathosus and Sjögren’s syndrome. Under the terms of the agreement, Servier shall provide ImmunoQure with an upfront payment and milestones amounting up to 164 million euros as well as royalties on net sales.

 

The technological platform

ImmunoQure focuses on the research and development of autoantibodies rescued from  patients suffering from an ultra-rare disease known as APECED/APS-1. APS-1 is a monogenetic disorder whereby null or hypomorphic mutations in the AIRE gene greatly impair central T cell tolerance. Consequently, APS-1 patients are unable to optimally delete self-reactive T cells, leading to an accumulation of T cells and B cells that target a wide range of self-proteins.
A seminal paper  published in Cell describes the autoantibody repertoire of APS-1 patients, including the presence of ultra-high affinity, biologically neutralizing, pan Interferon-alpha specific autoantibodies. “Our partnership has the potential to help large numbers of patients in several disease indications, and – very importantly – can directly aid APECED/APS1 patients by facilitating our greater understanding of their condition, and by demonstrating our capability to move from basic research investigations to clinical development” stated Professor Adrian Hayday, co-founder of ImmunoQure.

Greece: New measures on the entry of new medicines in the Greek market

Giuliana Miglierini
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Greece: New measures on the entry of new medicines in the Greek market

A year has gone from the announcement made on 14th December, 2016 by the Greek Government of a new policy on the launch of new innovative medicines. This may be delayed for up to four years, and products can only be introduced in Greece if they are reimbursed in at least 9 EU countries, half of which should be among Austria, Belgium, Great Britain, France, Spain, The Netherlands, Portugal, Sweden and Finland who participate in the Health Technology Assessment (HTA) system. New innovative medicines are also subject to an extra rebate of 25% for two years, that adds to the already present volume rebate of 20% and to a claw-back of 17% on average, for a total rebate of approx 60%.

What is happening on the companies’ side

According to the Hellenic Association of Pharmaceutical Companies (SFEE), the viability of the Greek pharmaceutical industry itself has reached to endpoint, with a high risk to be no longer sustainable. 

According to SFEE, none of the 43 new medicines launched in Greece in years 2014-2016, used to treat cancer and other rare diseases, meets the requirement of having a positive assessment by the HTA six countries as proposed by the Ministry of Health.
The Government’s measure might impact on the 87,000 jobs directly and indirectly supported by the Greek pharmaceutical industry. At the same time, it creates conditions of disinvestment and scaling-down of clinical trials currently under way in Greece. “What we call for is the advancement of the structural reforms needed by the country, instead of these policies that are revenue-collecting, anti-investment, irrational and dangerous for Greek patients and public health”, commented SFEE’s president, Mr Pascal Apostolides.
Pharmaceuticals are the solution and not the problem, is the position of the Hellenic Association of the Pharmaceutical Companies, as the sector actively contribute to social progress and make use of the country’s scientific potential, extroversion and job creation. Mr Pascal Apostolides urged the government to consider in a timely and pragmatic manner, the real consequences of its choices, “so that we don’t lose what wasn’t lost in the previous years of the crisis.”
According to Euractiv, many pharmaceutical companies are already considering to stop the supply of innovative drugs, and would even considering the possibility to withdraw existing drugs as a result of the rebates.
“Each company decides and designs its own commercial policy at national and European level. We once again request the Ministry of Health to immediately reconsider these measures and to proceed with the necessary structural policies, as they have been implemented successfully in several European countries”, wrote Mr Pascal Apostolides in a statement directed to the Greek Government.
According to FiercePharma, Roche already pulled in October 2017 the cancer drug cobimetinib from the Greek market. The medicine is a MEK inhibitor approved in 2015 to be used together with vemurafenib in patients with BRAF V600-mutation-positive advanced melanoma.
“Roche, a Swiss multinational pharmaceutical company, with an annual turnover in Greece of about € 200 millions, proceeded to an unacceptable and blackmailing move in withdrawing Cotellic from the reimbursement list”, declared the Greek Health minister, Mr Andreas Xanthos. He also pointed the attention to the fact that citizens’ access to innovative and effective medicines is not a business, but a political issue. “The provocative tactics used by Roche must be addressed with determination by all the political and social forces of the country and by all the European institutions as well. The Ministry of Health and the Greek goverment are already taking over political initiatives for not allowing this blackmail to take place. They ensure citizens that they will assure by any mean the continuation of the treatment to the patients who are already under this medicine and the secured pharmaceutical coverage to anyone in the future that will be indicated for the same treatment”, added Mr Andreas Xanthos.

Healthcare systems face significant challenges

Public pharmaceutical expenditure in Greece is now subject to a ceiling of € 1,945 million plus € 570 million for hospitals: an amount largely insufficient to provide up-to-date health treatments to patients. Out-of-pocket costs almost tripled from 9% in 2009 to 26% on average in 2015.
The other main priorities for the Greece healthcare system are the ageing of population, the increase of chronic diseases, the change in the Greek epidemiological profile, the rise of unemployment and the significant reduction in employers’ contribution, explained Mr Pascal Apostolides during the 16th Healthworld Conference, hold in Athens in October 2017.
Greece has also the lower annual average growth rate in per capita health expenditure (real terms, 2009 to 2015, OECD data): -6,6%, compared to 0,7% of EU 28, and the longest lead times for the approval of new medicines (about 21 months, compared with an EU average of 3.9 months).

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The first digital pill soon on the market

Giuliana Miglierini
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The first digital pill soon on the market

The era of digital medicines is here: the first “digital pill” was approved by the Food and Drug Administration on November 13th, 2017 and other technologies are under development in the research labs. The first product is expected to be launched on the U.S. market during 2018. We analyse how the yet approved product and a second one still under development approached the use of digital sensors to track compliance, and the issues still to be solved.

Otsuka’s aripiprazole tablet with sensor (credits: Otsuka Pharmaceuticals)

Intelligent tablets or capsules

The first FDA-approved product, Abilify MyCite (aripiprazole tablets with sensor), has been developed by Otsuka Pharmaceuticals in collaboration with Proteus Digital Health and it is indicated for the treatment of schizophrenia and bipolar disorder in adults.
The tablet embeds an ingestible event marker (IEM), a sensor that records the uptake of the medication. The liquids in the stomach activate the IEM, and the so-produced signals reach a wearable patch applied on patient’s skin, which records the date and time of the ingestion together with certain physiological data.
In a similar way, the ID-Cap technology under development by etectRx is activated at first and eventually dissolved by the organic fluids of the stomach after use to be eliminated through the patient’s GI tract. In this case, the ultra-thin, flexible and wireless sensor is embedded within the wall of a standard hard gelatin or HPMC capsule.
In both cases, the signals generated upon ingestion of the medicine reach a wearable reader, that for Abilify MyCite is embedded into a patch to be applied on the patient’s skin, while for ID-Cap it is a small device to be worn around the neck.

etectRx’s ID-Cap technology (credits: etectRx)

The tracking might fail

The plus of the digital pills should be represented by an enhanced compliance to treatment, but probably the technology still need to be refined to be fully reliable. According to Otsuka, it can take 30 minutes to 2 hours to detect ingestion of the tablet, but “sometimes the system might not detect that the medication has been taken”, tells the warning on the labelling of the product. In this instance, there is no need to repeat the uptake of the dose, is the advice of the manufacturer. But the point appears to be potentially controversial, as aripiprazole is a drug intended to treat schizophrenia, thus patients might be under altered mental conditions and it should be considered the risk of improper under- or over-dosage of the medicinal product. The approved labelling of the first digital pill also warns that the ability of the product to improve patient compliance with treatment regimen has not been shown. “The FDA supports the development and use of new technology in prescription drugs and is committed to working with companies to understand how technology might benefit patients and prescribers”, said Mitchell Mathis, director of the Division of Psychiatry Products in the FDA’s Center for Drug Evaluation and Research, in the note of the FDA announcing the approval.
Other warnings highlight the fact that Abilify My Cite is not suited to track drug ingestion in “real-time” or during an emergency because detection may be delayed or may not occur. A Boxed Warning is also present to alert health care professionals about the higher risk of death related to elderly patients with dementia-related psychosis (the product is not approved to treat this sort of patients) and the increased risk of suicidal thinking and behavior in children, adolescents and young adults taking antidepressants.

Dedicated apps to record information

In both case, an app installed on a smart device records the information transmitted from the Reader. The apps might also be accessed by caregivers, family members or clinicians – through a web portal in the case of the Otsuka’s product or a cloud-based Information Management Platform for the etectRx’s one – provided that patients gave their permission to access personal data. Furthermore, the FDA approval of Abilify MyCite only refers to the functions related to tracking drug ingestion, and not to the possibility to record also activity levels and self-reported mood or quality of rest.
The ID-Cap App can show reminders for the uptake of the medication and the history of adherence and allows customised messaging to individual patients, population health analytics, and clinical trial support.

A trial to track treatment with opioids

The ID-Cap technology has been tested in a pilot clinical study as a possible way to prevent opioid abuse, a major health issue in the United States that reached epidemics dimensions as for the diffusion of the over-dosage among population. The study conducted at the Brigham and Women’s Hospital (Boston, MA) included ten patients discharged from the emergency department after an acute bone fracture. The selected endpoint was a measure of patients’ as-needed opioid (oxycodone) ingestion patterns. The results have been published on the Journal of Medical Internet Research (doi:10.2196/jmir.7050) and appear to be encouraging: 96 ingestion events have been recorded over the one week study period (87.3%, 96/110 accuracy), with a mean ingestion of eight digital pills for each patient during the observed period. The majority of participants found the system acceptable (80%) and demonstrated a willingness to continue to use a digital pill to improve medication adherence monitoring (90%).

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The draft of the new Annex 1 is open to consultation

Giuliana Miglierini
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The draft of the new Annex 1 is open to consultation

The European Commission (EC) published on December 20th, 2017 the first complete revision of Annex 1 “Manufacture of Sterile Medicinal Products” of the EU Guideline for Good Manufacturing Practice (GMP) for drug products and drug substances. The draft is currently open to consultation until 20 March 2018. You can download it from this link.
The interested parties can provide their feedback by e-mail, writing to the address SANTE-REVISION-ANNEX-1@ec.europa.eu. It is also possible to send comments by post to the address “Directorate-General for Health and Food Safety, Unit SANTE B/4, BE-1049 Brussels”. In any case, the subject line should contain the reference “Targeted Public Consultation – Revision of annex 1 of EU GMP Guide”.
The template to be used for comments can be downloaded from the consultation web page, together with the instructions to fill it with relevant information for individuals or companies/organisations.

The structure of the new Annex 1

The revision of Annex 1 has been long waited, as since its original publication in 1971 the pharmaceutical technology has deeply evolved and new methods for production and analytical controls are now available and need to be considered in the relevant GMP regulations. This can be acknowledged by the fact that the new Annex 1 is a 50 pages long document, far more complex than the 16 pages old version (2008), and it includes many completely new clauses.
The GMP-GDP Inspectors Working Group of the European Medicines Agency started the revision in 2014 and drafted the final text of the new Annex 1 upon several steps of consultation of the interested parties and in collaboration with the World Health Organisation and PIC/S (Pharmaceutical Inspections Co-operation Scheme).
The new Annex 1 follows the Quality Risk Management (QRM, ICH Q9) principles typical of the modern pharmaceutical life cycle. The structure of the document has been completely revised to follow a logical flow and now includes specific sections discussing the requirements of Pharmaceutical quality systems (PQS, ICH Q10), the characteristics of single use and barrier technologies such as Rabs or isolators, and of the different type of sterilisation process, including form-fill-seal, blow-fill-seal and lyophilisation processes. The high level structure of the new Annex 1 is the following:

Section Number

General overview

1. Scope

Additional areas (other than sterile medicinal products) where the general principles of the annex can be applied.

2. Principle

General principles as applied to the manufacture of medicinal products.

3. Pharmaceutical Quality System (PQS)

Highlights the specific requirements of the PQS when applied to sterile medicinal products.

4. Personnel

Guidance on the requirements for specific training, knowledge and skills. Also gives guidance to the qualification of personnel.

5. Premises

General guidance regarding the specific needs for premises design and also guidance on the qualification of premises including the use of barrier technology.

6. Equipment

General guidance on the design and operation of equipment.

7. Utilities

Guidance with regards to the special requirements of utilities such as water, air and vacuum.

8. Production and specific technologies

Discusses the approaches to be taken with regards to aseptic and terminal sterilisation processes. Also discusses different technologies such as lyophilization and Blow Fill Seal (BFS) where specific requirements may be required. Discusses approaches to sterilization of products, equipment and packaging components.

9. Viable and non-viable environmental and process monitoring

This section differs from guidance given in section 5 in that the guidance here applies to ongoing routine monitoring with regards to the setting of alert limits and reviewing trend data. The section also gives guidance on the requirements of Aseptic Process Simulation.
10. Quality control (QC)

Gives guidance on some of the specific Quality Control requirements relating to sterile medicinal products.

11. Glossary

Explanation of specific terminology.

The document’s scope can be also extended to specific cases of the manufacturing of not-sterile medicinal products, that are discussed at the beginning of the new guideline.
The environmental control and monitoring requirements now ask to check the ≥ 5 µm particles during routine testing only of non-living particles, and not during qualification of the clean rooms.
Attention is also deserved to the qualification and validation of both terminal sterilisation and aseptic process (including simulation of this last one, where media fill is also included), and to cleaning validation.
The new Annex 1 might have an impact on manufacturing activities, as it requires to move towards a more holistic vision of the entire process based on a robust risk assessment for each step of the process and on the availability of the supporting documentation for all decisions. Among the main new points to be considered, the document introduces the requirement of a formal contamination control strategy and a cleanroom classification to be run according to the new ISO 14644 standards.

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Updates on the Brexit procedure

Giuliana Miglierini
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0
Updates on the Brexit procedure

The European Medicines Agency (EMA) new location will be Amsterdam, but the buildings (also the temporary ones) seems to be far to be available by March 2019, when the Brexit should finally occur. The decision of the European Council of November 20th, 2017 was taken at draw and left Milan defeated, the favourite city under the technical contents of the candidature dossier.

EMA updated the Q&A

After the decision, ΕΜΑ published an update to the Questions & Answers (EMA/478309/2017) for companies providing practical guidance for the procedures related to Brexit for medicinal products within the framework of the Centralised Procedure (CP).
Pharmaceutical companies are required to update their authorisation dossiers, as well as the investigational ones, in time to be ready from the regulatory point of view to meet the new requirements that shall come into force from 30 March 2019. It is not yet known how UK will position within the trade market after that date, thus the scenario considered in the guideline is referred to an hypothetical “third country”.
According to the document, companies can group different Brexit-related variations provided that the grouping does not delay implementation of changes which need to be in place by the time of UK’s withdrawal. EMA advices to check relevant details with the Procedure Manager (for products intended for human use) or the write to the e-mail address vet.applications@ema.europe.ue for the veterinary ones.

Each batch of finished product must be certified by a Qualified Person (QP) within the European Economic Area (EEA) before being released for placing on the market in the EEA or for export. Also the site for batch control needs to be located in the EEA or a country covered by a Mutual Recognition Agreement (MRA). Variations have to be filed to meet these requirements for products manufactured and/or released in UK.

The guideline also provides a table to classify Brexit-related changes impacting on the manufacturing activities. Introduction of a new manufacturing site for the active substance or for the finished product and their respective consequential changes can be submitted as a Type II variation separately for the active substance and for the finished product, thereby replacing a large grouping of Quality IB (and IA) variations for the consequential changes.
A Marketing Authorisation Holder (MAH) currently established in the UK will need to be replaced with an MAH established in one of the remaining countries of the EEA. In this respect a proof of establishment for the new MAH within the EEA, issued in accordance with national provisions will need to be provided as one of the supporting documents for the transfer application. Timelines for the transfer are to be agreed during the transfer procedure, but in any case the procedure must be fully completed and implemented by MAH before 30 March 2019. In case the transfer procedure concerns a medicinal product whose name is constructed as [international non-proprietary name (INN) / common name + name of the MAH], it may need changes to reflect the name of the Transferee.

Regulatory procedures can run in parallel with the Brexit-related marketing authorisation transfer application, provided the due consideration to avoid that the decision making processes of the procedures will overlap. An application for transfer of orphan designation has to be submitted at the latest in parallel with the application for transfer of the Marketing Authorisation (MA) since the opinion on the orphan designation transfer has to be reached before the opinion on the MA transfer. Sponsors currently established in the UK will need to be replaced with a new sponsor established in one of the remaining EEA countries, at the latest by the date on which the UK leaves the Union.
To facilitate handling of a large volume of transfer applications, a combined version of each required supportive document (except product information and, when applicable, mock-ups) can be created covering all products affected. The combined supportive documents should be submitted with each related transfer application and a declaration should be included in the cover letter, listing the related parallel transfer applications and confirming that supportive documents are identical.
The Qualified Person for Pharmacovigilance (QPPV) must reside and carry out his/her tasks in an EEA member State, as well as the Pharmacovigilance Master File (PSMF) location. Upon a change in the QPPV or location of the PMSF, the Article 57 database should be updated by the MAH immediately to allow continuous supervision by the Competent Authorities. There is no fee to be paid for updates in Article 57 database.

The point of view of the industry associations

A “no deal” scenario will deeply affect the supply of medicines for patients in the EU, according to a survey by the European Federation of Pharmaceutical Industries and Associations (EFPIA).
About 70% of EU investigational products are released from the UK, and there are 1,500 ongoing EU clinical trials with UK as sponsor (50% of those expected to be still active in March 2019). There are approx. 1,300 authorised EU products tested and released from Britain. The MAHs of centrally authorised products based in UK are approx. 400, and 45 millions of patients packs are supplied every month from the UK to EU countries. According to the report, 45% of EFPIA members expect trade delays in the supply of medicines if Britain will move to WTO rules. The 60% of the members of the Association also have a batch release based in the UK.

The associations representing the European and British life science industry (AESGP, ABPI, BIA, BGMA, EBE, EFPIA, EUCOPE, EuropaBio, Medicines for Europe, PAGB, Vaccines Europe) also published a joint policy document on the potential impact of the Brexit.
Medicines should be a priority in phase 2 of the Article 50 negotiations between Britain and the European Union, they jointly ask, and focusing on the framework for transitional arrangements and future relations with the UK must also be considered as it will be critical in ensuring a minimal disruption to patients receiving medicines after the Brexit will occur. With this regard, the warning is to keep in mind during negotiations the integrated nature of the supply chains for medicines across Europe. Among other key priorities are the close cooperation in ensuring that patients in the EU and the UK can continue to access medicines, a trade scheme appropriate to the movement of medicines between both regions, the possibility for UK to remain in the single market or in a new legal arrangement with the EU based on consistency of regulatory frameworks and aligned IP systems in order to avoid uncertainties for industry.

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