Giuliana Miglierini, Autore a NCF International

The sustainability of the business model for advanced therapies

Politics & Business

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20 September 2018

The sustainability of the business model for advanced therapies

A very hot debate is ongoing on the future sustainability of innovative therapies, particularly gene and cellular therapies (which goes together under the term “advanced therapies”, or ATMPs). The answer might be “No”, according to Goldman Sachs’ report “The Genome Revolution”. There is a potential $5 trillion total addressable market for genome medicines, said Goldman Sachs analyst Salveen Ritcher, and the social impact is expected to be very high. The problem is that ATMPs – especially gene therapies and in perspective also CRISPR-based gene editing medicines (which are expected to enter clinical trials by the end of the year/beginning of 2019) – are possibly curative and might hopefully resolve many medical issues of the patients. But on the other hand, despite their high prices, these medicinal products are unable to provide recurrent revenues to biopharmaceutical companies as therapies for chronic diseases did. Goldman Sachs’ report suggests three different potential solutions, as reported by CNBC journalist Tae Kim: address large markets such as hemophilia, address disorders with high incidence such as spinal muscular atrophy, or invest in constant innovation and portfolio expansion, for example to treat the hundreds of inherited retinal diseases.

CAR-T cell therapies under the lens

At the end of August 2018, Novartis’ first commercial CAR-T cell therapy (tisagenlecleucel, Kymriah) was approved also in Europe by the European Medicine Agency under the Prime scheme to treat pediatric and young adults with B-cell acute lymphoblastic leukemia (ALL, refractory or relapsed) and adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy.
The approval follows the one in the US in August 2017 for the paediatric indication, followed some months later by the approval to treat DLBCL in adults. Novartis has reported for Kymriah an income of $ 12 million in its Q1 financial results report, and $16 million for Q2. According to the Reuters, the company had initially much higher expectations of economic returns. Novartis said it will continue to collaborate with national health and reimbursement authorities across Europe on a fair, value-based pricing approach that is sustainable for national healthcare systems. A first example of this is the deal closed with NHS England at the beginning of September (see below).

In the US, Kymriah for ALL indication has been initially priced at $475,000, providing also an option to safeguard hospitals in case of inefficacy of the treatment. The price for use in DLBCL decreased to $373,000, equal to the one of the competing product from Gilead (axicabtagene ciloleucel, Yescarta), This last one was estimated to reach up to $ 250 million revenues in 2018, said the Reuters. Gilead’s product was launched in the United States in October 2017 and generated $68 million in sales during the second quarter of 2018, according to Gilead’s Q2 financial results.

Prices mentioned above refer just to the medicine, and do not include hospitals’ costs for the administration of the therapy and the complex management of patients, that have to undergo preparation and might experience severe adverse effects. According to an estimate published in the July issue of JAMA Oncology, these additional “non-drug” costs for CAR-T cell therapies are about $30,000 to $35,000. Are these numbers correct? Additional costs would be greatly underestimated according to Samuel Silver, an expert from the University of Michigan Comprehensive Cancer Center interviewed by Nick Mulcahy on Medscape, and the total cost for CAR-T cell therapies would be at least $750,000.

UK’s NICE rejected Gilead’s CAR-T therapy

A first official stop to Gilead’s Yescarta CAR-T therapy to treat diffuse large B-cell lymphoma came at the end of August 2018 from UK’s health technology assessment authority National Institute for Health and Care Excellence (NICE), that published the draft cost-efficacy analysis for the product. The final results of the procedure are expected to be available by the end of 2018.

According to the document, Gilead’s product reflects criteria to be considered a therapy able to increase the survival of terminal patients, but cost-efficacy estimates fall outside the range considered normal in order to access the Cancer Drugs Fund economical resources of the National Health Service (NHS). NICE, thus, did not recommended Yescarta to treat new patients affected by DLBCL within the NHS, while the ones already under treatment can continue their therapy. “People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop”, also states the draft report.

Just a week after NICE’s decision on Gilead’s Yescarta, the competitor Novartis reached with NHS England the first commercial agreement in Europe to made available its CAR-T cell therapy Kymriah for the paediatric indication. The commercial terms of the deal have not been disclosed; the full UK list price for Kymriah is 282,000 pounds per patient. “This constructive fast-track negotiation also shows how responsible and flexible life sciences companies can succeed – in partnership with the NHS – to make revolutionary treatments available to patients.”, said Simon Stevens, chief executive of NHS England.

GSK sold the ATMP pipeline for rare diseases

In the mean time, in April 2018 GSK sold its pipeline of advanced therapies for rare disease to Orchard Therapeutics; the deal is the result of the strategic review of GSK’s rare disease unit made in July 2017, thus confirming the difficulty of traditional pharmaceutical companies to sustain this sort of business model. The British multinational will now focus its pharmaceuticals pipeline on priority programmes in respiratory and HIV/infectious diseases, and on two other potential areas, oncology and immuno-inflammation.

But the exit of GSK from the field of rare disease is not complete, as the multinational became an investor in Orchard Therapeutics, receiving a 19.9% equity stake along with a seat on the company’s board, and it will also receive royalties and commercial milestone payments related to the acquired portfolio.
Orchard is a UK-US-based clinical-stage biotech company that received in 2015 a $19 million grant from the California Institute of Regenerative Medicine (CIRM) to advance its autologous ex vivo lentiviral gene therapy in ADA-SCID. In 2017, Orchard raised other $110 million in a Series B round of funding to further develop its pipeline in parallel with enhancing manufacturing capabilities.

The ATMP portfolio acquired by Orchard includes Strimvelis – the first autologous ex vivo gene therapy approved by EMA in 2016 for children with adenosine deaminase severe combined immunodeficiency (ADA-SCID) – two late-stage clinical programmes in ongoing registrational studies for metachromatic leukodystrophy and Wiskott Aldrich syndrome, and one clinical programme for beta thalassaemia. All the projects were initially part of a collaboration agreement signed in 2010 between GSK and the Italian non-profit charity Telethon and research institution Tiget – Ospedale San Raffaele, Milan. Other three additional Tiget’s preclinical programmes on mucopolysaccharidosis type 1, chronic granulomatous disease and globoid cell leukodystrophy will be acquired by Orchard under exclusive license upon completion of clinical proof of concept studies. Telethon/Tiget maintains the intellectual property on the products, while Orchard shall secure the continued development of the programmes and access for patients. Orchard also acquired GSK’s collaboration agreement with Molmed, the Italian biopharmaceutical manufacturing site for all the programmes interested by the deal.

In search of new business models

What is clear from the above mentioned examples is that the business model of next-generation biopharmaceutical companies focusing on advanced therapies has to be dramatically different than the traditional one in order to be sustainable. It is not yet clear what the result of this transformation would be, but the first proposals are starting to emerge to boost the debate among the stakeholders in view to the identification of a consensus position. An example is the recent “Health Economic Impact Landscape Analysis of regenerative medicine advanced therapy” published by the ARM Foundation for Cell and Gene Medicine in collaboration with IQVIA.
The report is based on a comprehensive review of published academic literature, health technology assessments and value frameworks related to the global health economic impact of ATMPs, with the final goal to provide a robust, “value-based” reference framework to measure and forecast the effect of breakthrough and potentially curative therapies on national and global healthcare economies.

According to the report, the change of paradigm towards an increased adoption of advanced therapies requires to re-think inputs of economical models of market access in order to accurately define the value of the new products. These inputs have to be validated to become routine tools for the assessment of new technologies: a challenge for manufactures, that have to win the skepticism about high upfront costs of ATMP products compared to their yet unclear economical value. This sort of dynamic is clearly represented by the above mentioned NICE negative assessment of the Gilead’s CAR-T therapy. Suboptimal patients access and reimbursement schemes are other issues to be addressed.

According to AMR and IQVIA, there are three different archetypes needing to be overcome, the strictly pharmaco-economic one (typical of UK, Canada and Brasil), the assessment of the clinical benefit in comparison to an authorised reference medicinal product (typical of the great part of European countries and Japan) and the “willingness-to-pay” approach typical of the US and China. A further barrier is represented by the high fragmentation of health technology assessment models and authorities across different countries, thus resulting in the possible divergence of results.
The suggestion is that, together with compulsory clinical evidence of safety and efficacy, also data on the cost-benefit ratio and impact on budget expenditure might be provided by companies under the regulatory process. Industrial costs might be also better considered, while by now are generally not required.

The analysis made by AMR and IQVIA identified a dozen indicators useful to better estimate the macro-economical framework and the fair value of ATMPs, and which are currently not considered in HTA analysis. They include a long-term period cost-efficacy evaluation, the redefinition of the value on the base of the curative nature of the therapies, the availability of patient-centred endpoints, including indirect costs and non-medical costs afforded by both patients and caregivers (e.g. loss of productivity or education, transports, home assistance, etc.), new models for payment and the availability of real-world evidence.
“Payments for performance” (P4P) is the suggested approach to better manage financial resources, as this model might win the skepticism of payers on the long term outcomes of the therapies. Annual installments of payments might also help to reduce the short-term impact on budgets (but not the long-term sustainability). Retrospective analysis, cohort observational studies and registries studies might also prove useful to acquire a better real-world evidence on the efficacy of ATMPs therapies.

Regulators launched activities to prepare for the Brexit

Regulatory

Giuliana Miglierini

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20 September 2018

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Regulators launched activities to prepare for the Brexit

Just six months are missing to the date of the Brexit, that will see Great Britain officially leaving the European Union from 30 March 2019. The impact on regulatory activities is expected to be relevant, as by the same date the European Medicines Agency (EMA) shall also complete the move to its new seat in Amsterdam. The transfer won’t be painless, and EMA announced in early August the expected staff loss might reach 30%, much higher than expected. In addition, due to the employment rules in the Netherlands, 135 short-term contract staff will no longer be able to work for the European Medicines Agency.

EMA will fully implement phase 3 of its business continuity plan by no later than 1 October 2018 in order to better afford relocation challenges: this will include the scaling back or even the temporary suspension of not essential activities. According to the Agency, core activities related to the evaluation and supervision of medicines will be safeguarded. The impacted activities shall include clinical data publication, collaboration at the international level, development and revision of guidelines and non-product-related working parties.

No further assessment contracts with MHRA

The situation in the UK has been further put under pressure by EMA’s decision to close the collaboration with the local Medicines & Healthcare products Regulatory Agency (MHRA) well before the date of the Brexit. MHRA up to now handled around 20% of the EMA’s workload. “We couldn’t even allocate the work now for new drugs because the expert has to be available throughout the evaluation period and sometimes that can take a year,” said a spokeswoman from EMA, as reported by The Guardian.

MHRA will not be allowed to accept new assessment contracts, and is also preparing to hand over existing drug review work to other countries, as well as transferring experts’ knowledge to the newly in charged counterparts. The UK’s agency played an essential role in the European network for the evaluation of human and veterinary medicinal products under the decentralised procedure and the mutual recognition procedure (and run one third of inspections), but the trend already slowed down in 2018. MHRA obtained only two contracts this year (on a total of 36 bids), said The Guardian. The decline started already in 2017, with just 6 contracts on a total of 90 applications for new medicinal products, if compared to the 22 contracts and 114 applications of 2016.
The estimate loss of funding for MHRA is about £14m (of a total budget of around £170M), added The Guardian. According to the current situation pointing towards a hard Brexit, from 30 March the UK’s agency will be the only responsible for the evaluation of medicines to be used by British patients, as authorisations released by EMA and other European national regulators will be no longer valid. Mike Thompson, chief executive of the Association of British Pharmaceutical Industry (ABPI), told The Guardian “companies are having to build extra laboratories to try to prepare to batch-release medicines made in the UK on the continent, an exercise implying very high costs to be sustained”.
According to labiotech.eu, a spokesperson for the ABPI commented that the long-term impact of EMA leaving London will depend on the nature of the future relationship with the EU on the regulation of medicines. “We want to see the UK play as full a role as possible as part of a future relationship which includes cooperation on regulating medicines and protecting public health.”, said the spokesperson.

Dutch Medicines Evaluation Board prepares for a deeper involvement with EMA’s activities

On the other side of the game, in the Netherlands the local regulator Medicines Evaluation Board (MEB) is preparing to overtake MHRA in a closer collaboration with EMA. “It’s a real challenge, but I’m not going to say there is not enough knowledge to replace that in the rest of the network”, MEB’s executive director Hugo Hurts told the Reuters.
The Dutch authority too is preparing for a hard Brexit, as explained by a note released at the beginning of September, with the main priority to safeguard the quality, safety and efficacy of medicinal products.

At the moment there is still a great deal of uncertainty about the consequences of Brexit for the MEB, states the note, but its internal capacity has been already reinforced to prepare for the worst-case scenario. To better afford the challenge, all projects and activities relating to Brexit and the relocation of the EMA to Amsterdam have been accommodated into a specific programme to ensure continuity of the MEB’s work and minimise impact for patients. Combining various projects and activities should lead to better (internal) coordination, cohesion and a more effective way of working, is the approach taken by the Dutch agency.

Reinforce the European cooperation

The 20% assessment procedures left behind by MHRA are currently being divided among the remaining 27 EU Member States (see the article in the May 2018 EIPG newsletter).
MEB and the Dutch government are also collaborating to sustain a number of Member States to improve their regulatory capacity. “Brexit is certainly also an opportunity to reinforce cooperation with other European medicines authorities,” said Hugo Hurts. “The MEB is not only focusing on expanding its own capacity. We also want to distribute the work more effectively among the various European medicines authorities. By doing so we also intend to build up long-term relationships for future cooperation in terms of flexible distribution of work in the area of multinational assessments.”
The provision of capacity and training on the issues of pharmacovigilance, quality and pharmacology, toxicology and kinetics appears to be the priorities to be addressed under the Memorandum of Understanding signed by now between the MEB and nine countries (Malta, Iceland, Estonia, Latvia, Lithuania, Slovenia, Croatia, Slovakia and Bulgaria). Small European countries are so expected to gradually assume a stronger role as Reference Member States in managing decentralised procedures (DCP). The activities to reinforce the network of national evaluation authorities will be funded by the Dutch government, which set aside €10 million.

The last agreement, signed with Lithuania, has been the first signed at the level of Health Ministers. ”The Netherlands is a minor player in this field, but by joining forces with other countries, we can ensure that medication gets to the patients who need it sooner, more cheaply and more safely.”, said Dutch Minister, Bruno Bruins. Under the agreement, the two countries will also become partners to broaden market access to certain medicines, so that drugs that are marketed in the Netherlands will also be available straightaway in Lithuania. This action from the Dutch government is intended to provide access to medicines also in countries that generate less sales volumes, and are thus often not included into the marketing strategies planned by pharmaceutical companies.

The action plan of the HMA/EMA task force

The Work programme for years 2019/2020 of the HMA/EMA task force on availability of authorised medicines for human and veterinary use also contains some actions specifically designed to achieve a smooth Brexit transition.

The provision of practical guidance to implement regulatory changes required following Brexit (e.g. change of reference member states) is planned for Q4 2018, together with the target of a minimal disruption to medicines supply and actions to avoid shortages of authorised medicines in the European Union. At a later stage, in Q2 2019, best practice guidance for regulators should be also developed on the sharing of information within the EU regulatory network.
The task force is a working group composed of representatives from the national competent authorities, EMA and the European Commission, as well as the Chairs of the medicines regulatory bodies representing the European Union (EU) member states, Iceland, Liechtenstein and Norway.
The task force operates under three thematic working groups, each in charge of different aspects of the prevention of shortages of medicinal products. The areas of competence include the implementation of the current regulatory framework in order to approve new drugs and the study of measures to prevent stock disruptions. The Communication working group should complete by the end of the year the mapping and analysis of current public communication practices used by EMA and individual national competent authorities to communicate themes linked to the availability and shortage of medicines. A web page detailing activities of the task force should be also created on the websites of both EMA and HMA.

An EMA’s workshop is planned for 8-9 November to debate the work programme with all the interested stakeholders. A reflection paper has also been published by EMA together with the work programme, which better analyses reasons at the base of drug shortages in the EU and the available options to mitigate them. The failing or withdrawal of authorisation in some Member States, or companies giving up marketing of authorised products in less interesting countries, are among the possible causes addressed in the document. A possible way to solve the issue is represented by the above mentioned collaboration agreements signed by the Dutch government with small European countries

Trends in the European medical technology industry, 2018

Technology & Production

Giuliana Miglierini

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20 September 2018

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Trends in the European medical technology industry, 2018

The European association of the medical technology industry, Medtech Europe, has published its 2018 report, showing the leadership of the EU’s medtech sector as represented by the number of patents applications filed with the European Patent Office (EPO) in 2016 (12,200, corresponding to 7.7% of total). The document refers to medical devices and in vitro diagnostics, corresponding to more than half million different technologies available on the market.

The number of patents for medical technologies more than doubles applications for both the pharmaceutical and biotechnology fields (around 5,700 each). Medtech patent applications greatly increased in the past decade, while those for the other two health sectors remained quite constant. Analysing the origin of applications for medtech patents, 59% came from extra-EU countries (38% from the US), and just 41% were filed from European countries (EU28, Norway and Switzerland). Patent applications for medical technologies also greatly overcame the ones for digital communication (10,900) and computer technology (10,600); pharma and biotech patents are far behind in the ranking, after also electrical machinery, apparatus and energy, transport, measurement, engines and organic fine chemistry.

SMEs are predominant

The medical technology sector employs in Europe 675,000 people (just less of the 740,000 of the pharmaceutical industry), mainly in Germany (210,000), UK (100,000), France (85,000) and Italy (76,000). The number of employees per capita is highest in Ireland (35,000) and Switzerland (54,000).
There are more than 27,000 medical technology companies active in Europe, 95% of which are SMEs, e.g. companies with less than 250 employees and an annual turnover not exceeding €50 million. Among these SMEs, the great majority are small and micro-sized companies, employing not more than 50 workers. The European medtech industry is mainly based in Germany, UK, Italy, Switzerland, France and Spain.

The market and expenditure in medical technologies

The total value of the European market for medical technologies in 2016 was approx. € 110 billion (upon manufacturer prices), corresponding to around the 29% of the world market and ranking second after the US (approx. 43%).
Germany is the leader among European countries (28% market share for medical devices), before France (15%), UK (12%), Italy (10%) and Spain (6%); all other countries count for no more than 4%. The overall medtech market follows a similar trend, as well as the market for in vitro diagnostics.
The sector attracts less than 1% of gross domestic product (GDP), whereas the healthcare expenditure counts for an average of 10% of GDP. More than three fourths of the total European healthcare expenditure (76,9%) relates to inpatient and outpatient care and other applications, 15,9% to pharmaceuticals and other medical non-durables, 7,2% to medical technologies (6,5% of which to medical devices, including imaging) and just 0,7% to in vitro diagnostics.
The European weighted average per capita expenditure in medtech is € 203, with great differences among different European countries, ranging from around 5% to 10% of the total healthcare expenditure.

A positive trade surplus

The medical technology sector generated an estimated positive trade surplus of € 17.5 billion in 2016, with the exclusion of in vitro diagnostics, a twofold increase since 2006 and more than the triple with respect to the US (€5 billion). The United States (36,9%), China (10,3%) and Japan (5,4%) remain the preferred partners for the European export of medical devices. A similar trend was observed in 2016 for imports, being the US the greater contributor (55%).
Once again, Germany is leading the internal EU’s ranking for both exports (especially) and imports of medical devices (€ 25 mln exports, € 16,4 mln imports respectively, including intra-Community trade), far above the Netherlands (€ 15,6 mln and €12,9 mln, respectively), Belgium and Ireland. This last country shows a positive trade balance very similar to the one of Germany (€ 8,6 mln); on the opposite site, France, Spain, UK and Italy showed in 2016 the most negative trade balance for medical devices.

Netherlands: The Dutch approach to expensive medicines

Focus on EU’s Countries

Giuliana Miglierini

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20 September 2018

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Netherlands: The Dutch approach to expensive medicines

The Netherlands is not immune from the problem of the high prices of advanced therapies and drugs for orphan indications. The most recent case saw the identification by a research group from the Antoni van Leeuwenhoek (AvL) hospital in Amsterdam and the Oncode Institute of the possibility to target melanoma cancer cells resistant to standard treatments with the histone deacetylase inhibitor vorinostat (Zolinza®), an anticancer drug marketed by Merck.

The vorinostat case

Vorinostat received an orphan designation in 2004 by EMA to treat cutaneous T-cell lymphoma; the application for approval in Europe was withdrawn by Merck in 2009. The drug was approved in 2006 in the US for the same indication by the Food and Drug Administration (FDA).
Being the indication to treat melanoma different than the approved one, and upon consideration that vorinostat is not available in the Netherlands and has a cost of $ 100-125 per capsule in the US, AvL hospital decided to produce it within its internal pharmacy to be used for planned clinical trials. This allowed to drop down the costs of the medicinal product to € 2,5 per capsule, meaning a total of € 10 for the 4 capsules needed per day treatment. A dramatic difference if compared to the $ 400-500 of the daily therapy in the US.
According to an article by de Volkskrant, the approach used by AvL was possible due to the fact the patent protection for vorinostat active ingredient has already expired. The journal also reports that AvL has already negotiated exclusivity with the FDA to treat the melanoma indication and is looking for a manufacturer to produce the product. Merck, on the other hand, is said to had replied that “Although this medicine is still on the market, we no longer promote it and no longer carry out any studies with it.”

A new way is open

Dutch hospitals and academic medical centres have a long tradition of pharmaceutical production within their internal pharmacies, and many of them possess a manufacturing license and GMP Certificate. Until now hospitals have been only entitled to manufacture drugs that are not provided in the Netherlands by a commercial party, but the situation is rapidly evolving as the result of the need for responsible and sustainable answers to the continuous increase of drug prices.
Earlier this year a similar case occurred at the academic hospital Amsterdam Medical Center (AMC), that in April 2018 started its own production of the drug chenodeoxycholic acid (CDCA) to treat the rare hereditary chronic metabolic disorder cerebrotendineous xanthomatosis (CTX). The commercial product is owned by Leadiant Biosciences (previously known as Sigma-Tau) and was approved in April 2017 by EMA as an orphan drug to treat CTX using the ‘exceptional circumstances’ procedure. But the active ingredient is not new, and its off label use dates back to the 1970s (see below). The approval as an orphan drug has entitled Leadiant to obtain a 10 years exclusivity on the product to treat CTX, even if the patents on the active ingredient have already expired.

A matter of reimbursement

According to AMC, the decision to manufacture the medicine in its pharmacy came after Leadiant product was no longer reimbursed by Dutch insurers due to the approximately fivefold increase of its price after the medicine had been registered as an orphan drug. The previous cost was approx. € 30-40,000 per year treatment. According to AMC, the equivalent product prepared by the hospital is reimbursed. Carla Hollak, professor of hereditary metabolic diseases and one of the initiators of the project at AMC, commented that “This price increase has no relationship whatsoever with additional costs or added value of this registered product compared to the previously prepared drug.”. The case has also been reported on the columns of the British Medical Journal.
But the set up of the internal production had to face the difficulty to find a supplier of the active ingredient, which had been finally found in China. This, according to AMC, had been inspected by a delegation from the Netherlands, and the active substance checked by a European laboratory to verify respondence to European quality requirements.

The recall after an enforcement inspection

In June 2018 the AMC manufacturing facilities were inspected by the Governmental Dutch Health Care and Youth Inspectorate (IGJ). Results of the inspection were published in August, indicating AMC’s product did not meet the legal requirements of the European Pharmacopoeia as some unknown impurities above specifications were present in the active ingredient. In addition, AMC is claimed not to had investigate whether the active substance met the general monograph ‘Substances for Pharmaceutical use‘ from the European Pharmacopoeia.
The enforcement inspection was activated by IGJ upon a written request by Leadiant, acting as interested party protecting its market. “We have tested the ingredient thoroughly to ensure it meets European standards via a certified laboratory. We are surprised that the inspectors have reached a different decision.”, commented AMC board member Frida van den Maagdenberg, as reported by the online journal DutchNews.nl.

According to ncr.nl, after Dutch insurers angrily replied to AMC’s decision to recall the product following the inspection, some of the insurers are now supporting the possibility AMC and the Inspectorate can come to an agreement about new preparations for the medicine.

The political debate

Dutch Minister of Health Bruno Bruins in November 2017 told the Parliament about the intention to use compulsory licensing of patents of too expensive medicines as a possible tool to overcome the issue, reports Medicines Law and Policy. The reason to activate this sort of procedure might be find in the public interest to access “absurd pricing” of needed medicines. The position taken by Minister Bruins followed the publication of the report “Development of new medicines: Better, faster, cheaper” by the Netherlands Council for Public Health and Society, and of a second report on the pharmaceutical industry prepared by three opposition parties.

Previous Dutch Minister of Health Edith Schippers managed to include in the basic health insurance package the combination drug for cystic fibrosis lumacaftor/ivacaftor (Orkambi), after negotiating with the producing company Vertex a price lower than the official €170,000 per patient per year (read more on DutchNews.nl).

An official action to lower prices

Lowering the excessive pricing of many medicinal products is the mission of the recently established Pharmaceutical Accountability Foundation (PAF). Its first action, announces PAF from its website, will refer to the above mentioned case of chenodeoxycholic acid.
As reported by the Foundation, the branded product (Chenofalk) was marketed from 1976 to at least 2008 in the Netherlands at a cost of € 0.28 per capsule. From 1999, it was prescribed off-label for the treatment of CTX with a cost of € 308 per treatment per year. After acquisition of the product in 2008 by Sigma-Tau (now Leadiant), in 2015 the company removed it from the market to start again commercialisation in the Netherlands in 2017, with a price 500 times higher and following re-classification as an orphan drug. According to PAF’s chairman Wilbert Bannenberg, Leadiant’s behaviour is socially unacceptable. “Leadiant is abusing its dominant market position, and the Foundation will, therefore, submit an enforcement request to the Netherlands Authority for Consumers and Markets that can and should counter these abuses”, he said.

Pharma companies are not yet ready for the Brexit

Regulatory

Giuliana Miglierini

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2 August 2018

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Pharma companies are not yet ready for the Brexit

The European Medicines Agency published the results of the survey run from 23 January to 9 February 2018 among pharmaceutical companies which might be impacted by the Brexit. EMA submitted two distinct questionnaires to the interested companies, the first one intended to gather information on transfer of marketing authorisation holders (MAH), pharmacovigilance system master file (PSMF), qualified person for pharmacovigilance (QPPV), orphan designation and veterinary ‘minor use minor species’ (MUMS) designation changes. The second questionnaire aimed to gather information on manufacturing sites for batch release, importation, batch control, and on Official Medicines Control Laboratory (OMCL) testing arrangements.

According to the survey, marketing authorisation holders for more than half (58%) of the 694 centrally authorised products (CAPs) with an important step in their regulatory processes in the United Kingdom are on track with their regulatory planning to ensure that their MAs remains valid once the UK leaves the European Union. But many companies still lag behind in the activation of regulatory procedures in preparation to the leave.

The main results of the survey

Approximately 90% of the 180 companies contacted by EMA answered the survey; just 6% (27) of respondents plan to submit variations after the date of 29 March 2019, when the United Kingdom shall become a third country. According to EMA, 400 medicines require a transfer of the marketing authorisation to a MAH based in the EU or EEA member State.
The consequences of the Brexit might deeply affect the pharmaceutical business, as the EU law requires that marketing authorisation holders are established in the EU-27 or European economic area (EEA), and some activities (e.g. pharmacovigilance, batch release, quality control) must be performed in the same geographic areas.
As for the location of the qualified person for pharmacovigilance (QPPV), this has to be varied for 335 centrally authorised medicinal products (both human and veterinary); the great majority (84%) of changes is expected to be submitted on time. The location of the pharmacovigilance system master file (PSMF) for 376 medicines has also to be modified, and in this case 60% of respondents (224) said the change might not be made on time.
Batch release activities account for a lower number of variations needed (119), and should be mostly completed in time (81%). As for quality control, the interested site has to be changed for 41 CAPs; for 35 (85%) of them, MAHs are planning submission in due time. Just 18 products need to modify the importation site, and just half of the interested companies answered EMA’s survey, among which just 4 (22%) are expected to activate the procedure before the end of March 2019. According to the report, the majority of the changes related to the batch release, quality control and importation site are expected to be minor variations, except when related to biologicals. The majority of the 18 CAPs for veterinary products still did not planned exactly the time to submit changes.

A possible shortage of medicines on the EU market

In terms of intended submission dates, the majority of transfers for human medicinal products are expected by EMA to take place by Q2 2018. The European Medicines Agency has foreseen to handle the great part of the already filed variations by Q1 2019, in correspondence to the move to the new seat in Amsterdam. EMA thus urges companies to file the needed changes as soon as possible, and before the end of Q4 2018.
More specifically, according to EMA, MAH transfer submissions linked to the Brexit represent approximately a ten-fold increase compared to average annual submission levels. ‘Brexit’ variations represent an increase of 22% of Type IA and 10% of quality Type II variation submissions.
The report also indicates a high level of uncertainty as to where the new sites for PSMF, QPPV and batch release will be located post-Brexit: this information is important in order to allow the Agency and EU network inspectorates to plan their workload and resources.
Following up survey’s results, EMA is now separately contacting non-respondent companies in order to verify exactly their plans to afford the regulatory transition of their products. Contacts shall also be made with companies that declared the intention not to submit changes before 30 March 2019, as this could potentially lead to supply disruptions. The survey identified 108 critical products (16% of total, 88 human and 20 veterinary) that might pose issues for their supply in the European Union after the Brexit, as all (or a major part) of the Brexit-impacted steps are carried out in the UK only, and delays are possible in the timeframe to deposit the needed changes to dossiers.

Pre-clinical to clinical boundary, the key to success

Technology & Production

Giuliana Miglierini

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2 August 2018

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Pre-clinical to clinical boundary, the key to success

How to correctly identify the boundary between pre-clinical and clinical development, in order to optimise the rapid translation of research towards new and innovative medicines and develop new business models for the pharmaceutical industry? The question was addressed by a joint workshop held in March 2018 by the Academy of Medical Sciences and the Association of the British Pharmaceutical Industry (ABPI), those results have been published in the summary report “Bridging the preclinical-clinical boundary”.

A two-way exchange to better define the boundary

Translational research aims to optimise the pathway of candidate medicines from the lab to the final use in the clinical practice by investing in the optimisation of early-stage clinical development. This is based, according to the report, on four key pillars: an interdisciplinary workforce that spans across sectors; a research infrastructure that supports collaboration and knowledge exchange; an agile and flexible regulatory processes; and new technologies that provide opportunities to enhance preclinical and early clinical research.
The key point to be addressed is the correct identification of the boundary between pre-clinical and clinical phase, i.e. the point where there is sufficient pre-clinical evidence available to start first-in-human clinical trials.

Phase 1 and 2 studies – focused on the determination of the safety and efficacy profile of the candidate drug – present a particularly high risk and attrition, and require a significant escalation in both resourcing and time. A robust and predictive evidence is thus needed as a prerequisite in order to successfully plan following development steps and optimise the large costs of later stage, phases 2b and 3 clinical trials.
The suggestion coming from the workshop indicates the possibility to maximise progression by mean of a ‘two way’ evidence exchange across the boundary: evidence from pre-clinical models should closely shape the design of clinical studies, while data obtain from clinical studies (e.g. data on populations or drug interactions) should be used as a feedback to run further preclinical research. The final objective should be the improvement of the initial selection and validation of the target, the evidence of efficacy and identification of biomarkers.

An interdisciplinary and integrated team approach

The two-ways exchange model requires a strong integration of both research infrastructures and skilled interdisciplinary workforces at the pre-clinical and clinical level. The traditional model of development sees a quite deep separation between the pre-clinical and clinical functions, both at the level of the dedicated facilities and interactions of the respective staff. According to ABPI, the new collaborative model overcomes this separation to achieve a better integration of disciplines and sectors, scientific evidence generation and funding models. The effort to proceed in this direction may require different incentives and ways to reward ‘success’, as well as redefining career pathways. Training may be also needed in order to fill skills gaps, i.e. in bioinformatics, statistics, clinical pharmacology and pharmaceutical science. Early development teams should include a wide array of different skills, from basic scientists, project leads and regulatory experts to clinicians and statisticians. As explained by Professor Paul-Peter Tak, Chief Immunology Officer and Senior Vice President R&D Pipeline at GSK, the focus should be on the quality of a molecule based on its physicochemical properties, and the value of identifying the right early clinical studies that can better inform late stage development.
Another issue relates to the differences in culture traditionally experienced between the academia, industry and healthcare providers, which might make it hard to integrate the different perspectives. According to the results of the workshop, early engagement and a better appreciation of the respective cultures and differing priorities might help to overcome this division and to increase permeability across sectors. An example in this direction is the Open Targets platform, created by GKS in collaboration with the Sanger Institute and European Bioinformatics Institute with the goal to share knowledge and expertise to better identify and prioritise promising therapeutic targets.

The challenges of experimental medicine

Safety and efficacy data obtained from early stage clinical trials are used to inform the decision to further proceed with clinical development. The approach typical of experimental medicine requires a strong interaction between the industry and the academia and/or hospitals where the studies are run, and who often hold the expertise in biological pathways and physiology. Permeability across sectors is a goal achievable, according to the report, working to increase research culture, skills and awareness into early medical training and establishing appropriate incentives in the wider healthcare system. Access to the best available research infrastructure may be facilitated by the availability of ‘front door’ organisations (e.g. university translational research offices (TRO) and cluster organisations) supporting research sponsors to identify the right expertise.
Mutual recognition of success in early stage research should also be encouraged in order to fill the ‘credibility gap’ mentioned by Tim Eisen, Head of Oncology (Translational Medicine Unit) at AstraZeneca and professor of Medical Oncology at University of Cambridge: for experts from the academia, for example, it might be important to evaluate the progression of a therapy to the next stage of clinical development under the same terms of a publication in a high impact journal. Pre-competitive collaborations, open science and open innovation should be a goal for industry, in order to share excellence and high-quality data, especially at the more basic levels of research.

Complex infrastructures and new technologies

Another important point relates to the easy understanding of the complex research infrastructure network by all stakeholders, and particularly by SMEs, being the ones more likely to rely on collaborations to access the needed expertise. TROs might be very useful to provide a matrixed support team to help the navigation across the many activities linked to the proper management of the preclinical/clinical translational boundary, including preclinical validation, good manufacturing practices, good laboratory practice safety testing, regulatory knowledge and clinical trial infrastructure design and management.
From the financial point of view, a better targeting of funding would be needed in order to support scale-up and proof-of-concept of early clinical research and encourage further funding from venture capitalists and industry.
Many new pre-clinical technologies are already available to support a better integration of the boundary, i.e. the microphysiological systems (MPS) known as organ-on-a-chip, that mimics the complexities of human tissues and organs. They allow the preliminary evaluation of many parameters and physiological phenomenons before testing on the actual human tissue occurs. Such models might also be used to model pharmacokinetics and pharmacodynamics (PKPD) of a drug, and possibly to identify drug interactions and contraindications. The suggestion made by the report is that in future they might also supplement or even replace animal models.

An agile regulatory framework to support early stage trials

Early stage clinical trials might benefit from the ‘devolved health systems’ model to create pilot integrated schemes at a local level and provide flexibility to rapidly assess small, iterative improvements that may be otherwise too costly, slow or risky to be managed. Patient recruitment might be improved by a better engagement with patient groups, suggests the report, especially for experimental medicine studies which might not directly benefit the participant.
Flexibility to support innovative trial design should also come from the regulatory perspective, in order to adapt the design to actual outcomes data. This might include the possibility to remove or add treatment arms, change the balance of randomisation or alter statistical methodologies, without compromising validity. A collaborative approach that includes also regulators is thus suggested, for example by a better interaction with the MHRA’s Innovation Office. It would be also important to constantly inform regulators with technological developments that are likely to feature in licensing applications, such as the above mentioned organ-on-a-chip.

3D printing, a disruptive technology still lacking regulatory guidance in the EU

Regulatory

Giuliana Miglierini

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19 July 2018

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3D printing, a disruptive technology still lacking regulatory guidance in the EU

3D printing is transforming how products are made also in the pharmaceutical and, especially, medical technology sectors. The additive manufacturing process is quite complex and involves many different competences, from medical doctors called to prescribe the personalised intervention for each single patient to engineers working at the project, to software specialists that have to transform it in the form suitable to instruct the 3D printer to built the final object, to vendors of the 3D files. Material sciences are also a fundamental part of the game, as the properties of the starting materials used during the printing process are very different from those typical of bulk productions and have a great impact on the final characteristic of the product. The interactions among all these different stakeholder implies many regulatory and legal issues, both technical and regarding civil liability and intellectual property rights, that in great part still need to be clarified.

Pharma applications are the future of 3D printing

The first 3D printed medicine (and the only one up to now) was approved in 2015 by the FDA, a reformulation of the anti-epileptic seizure drug levetiracetam developed by Aprecia Pharmaceuticals.
Much more developed is the application of additive manufacturing in the field of medical devices, where the technique is already widely used to obtain, for example, personalised prosthesis on the base of the specific anatomical characteristics of each patient, or 3D printed scaffolds for regenerative medicine. A very interesting application of additive manufacturing, especially in the view of its possible future translation towards the production of pharmaceuticals, comes from the startup Multiply Labs and focuses on the automated production of 3D printed capsules containing personalised dietary supplements. Not surprisingly, the technology used by the Californian startup to obtain the controlled, retarded release capsules has originated from a long-standing tradition of research and development in the field of pharmaceutical technologies experienced by one of the founders during her university studies at the University of Milan, Italy (see here for more details). From the industrial point of view, an initial approach focused on dietary supplementation allows an easier regulatory development and lower barriers to enter the market for what appears to be a first-in-class technology offering many opportunities of further development also for the manufacturing of personalised medicines.
The full exploitation of 3D printing techniques in the pharmaceutical industry is still hampered mainly by regulatory reasons. If the FDA has started issuing guidelines, up to now focusing on medical devices, in the European Union the development of a common approach still lags behind. The EU Parliament recently announced to intention to work on a new legislative framework regulating 3D printing in order to better ensure safety of products for users.

The first guideline from the FDA focuses on devices

The first guideline specifically governing the additive manufacturing of medical devices was published in December 2017 by the Food and Drug Administration
The guideline came after at least an hundred products had been evaluated by the US regulatory agency and it offers the first structured reference framework for the development and production of 3D printed medical devices. The FDA Center for Drug Evaluation and Research (CDER) also received at least a dozen (formal and informal) requests from pharmaceutical companies to address the use of this disruptive technology also in view of its application to the manufacturing of medicinal products, according to the editorial signed by FDA’s Commissioner, Scott Gottlieb.
One possibility suggested by Mr Gottlieb is the possibility to use CDER’s Emerging Technology Program, aimed to support the rapid development of highly innovative approaches for design and production in the pharmaceutical field.
The guideline for medical devices was developed with the support of the 3D printing facility internal to the CDER and the one installed at the Center for Devices and Radiological Health (CDRH), that tested the impact of the different options available to the regulator on the final quality, safety and efficacy of the devices. The guideline is a “leap-frog” document, just the first step based on the current status of development of this innovative approach to manufacturing, and it will necessarily evolve in future years. FDA Commissioner already announced the intent to further explore the role on non traditional production sites, such as hospitals or university labs, and to deepen the evaluation of 3D printing techniques used to obtain advanced materials containing cells or other biological materials.

The design and manufacturing steps

The first section of the FDA guideline is specific to the “Design and Manufacturing Considerations” to be taken in mind while developing the quality requirements for 3D printed devices and their regulatory classification. Flow diagrams can be used to better explain the complex synergy of technologies and materials involved in the manufacturing, and each critical step may be further detailed by a summary, including used parameters, their interactions and the impact on final product, and the output specifications. A clear knowledge of each passage of production is essential, according to FDA, to allow the proper identification of root causes and consequent risks in case of defects. A discussion of the impact of imaging and of the modification of parameters of standard devices in order to adapt them to the anatomical characteristic of the patient is also provided.

The transfer of 3D files among the different players of the process presents also cybersecurity risks and protection of personal data that have to be considered during the development of the product. The guideline discusses also the requirements of the software used for additive manufacturing, as well as controls on starting materials and post-process controls and validation.

The content of the dossier

The second part of the guideline (“Device Testing Considerations”) is more focused on the information to be included in the premarket notification submission, to be developed according to different procedures depending on the classification of the device. Advice on the procedure to be used may be asked at e-mail DICE@fda.hhs.gov
Description of the device should always include its dimensional range, and critical dimensions that might undergo modification during patient-matched device’s production.
3D printed devices are subject to the same tests on the finished product as the one coming from traditional manufacturing, to be run after post-production, cleaning and sterilisation. Any worst-case choice of the device chosen for the tests have to be explained. The effect of the printing process and the positioning of the device within the internal “building space” of the printer should also be addressed, as they might impact on the final properties and functionality.

Biocompatibility of the finished product should be tested according to ISO 10993, and chemical modifications of the starting materials should be discussed as well as the possible risks for health coming from the use of polymers. Adhesion and cohesion forces have to be characterised, as they play a fundamental role for the integrity of the device. An evaluation of the microstructure is also required for metallic and ceramic materials, and morphology examination for the crystalline ones. Swelling water content is required for hydrogels and in vitro degradation tests are needed in case of devices printed using adsorbent materials. Post-production removal of accessory parts has to be evaluated, as it might result complex as a consequence of the structure of the device, impacting on the results of sterilisation.

Discussion is still behind in Europe

According to the European Commission, by 2021 the 3D printing market could be worth € 9.6 billion. In the European Union there is still no specific guideline available nor for the additive manufacturing of medical devices nor for pharmaceutical products. The production of medical devices currently follows the same standards used for serial production and custom-made devices, respectively. The debate on how to regulate additive manufacturing is still at the beginning in the EU. As reported by EMA’s “Annual report 2017”, the EU Innovation Offices Network (EU-IN, voluntary established by 23 national competent authorities) started discussions on emerging areas of innovation with expected impacts on regulatory evaluation standards and practices in the pharmaceutical sector and novel manufacturing strategies, among which 3D printing.

The European Parliament adopted on 3 July 2018 the report of French member Joëlle Bergeron containing legislative and regulatory recommendations in the field of 3D printing, at the level of civil liability and IP rights protection. The report will be now forwarded to the European Commission for consideration.
According to Bergeron (see here an interview published on the Parliament’s website), even if the rules on civil liability expressed by the e-commerce directive currently apply also to 3D printed products, more specific rules would help to better identify – in case of accidents – the person responsible for the defect. The protection of property rights of designers and printers and the fight to counterfeiting should be further points of attention for the European legislators.

According to the Bergeron’s report, 3D printing has not had a dramatic impact on copyright, but it “it would be wise to distinguish between home printing for private use and printing for commercial use, and between B2B services and B2C services”. A similar distinction is also suggested for liability, as civil liability is not harmonised and is subject to national legislation, while EU legislation covers more specifically civil liability for defective products. The suggestion made by the rapporteur is to pay a great attention in the definition of the accountability chain and the identification of those accountable when determining whether the general liability regime may continue to apply or not.
“It will take many years and a good deal of expertise before high-quality products can be made which do not pose a risk to users or consumers”, states the report. Accident liability or intellectual property infringement are other point that would require the adoption of a new legislation at EU level or the tailoring of existing laws to the specific case of 3D printing. Some suggestions made by the document include the creation of a global database of printable objects to control reproductions of copyright-protected 3D objects, the introduction of a legal limit on the number of private copies of 3D objects to prevent illegal reproductions, or the imposition of a tax on 3D printing to compensate IPR holders. “None is wholly satisfactory on its own”, specifies there report.

The new Horizon Europe is coming

Technology & Production

Giuliana Miglierini

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19 July 2018

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The first step towards the new European research framework programme Horizon Europe (FP9 2021-2027) has been undertaken by the European Commission with the publication of its proposal, that will continue the approach of the current Horizon 2020. The proposal is part of the wider one for next EU long-term budget, the multiannual financial framework (MFF), for a total value of € 100 billion to be spent for research and innovation (R&I). Horizon 2020 will be active for some two more years, while discussions will continue at the European institutions to reach the final agreement on the new budget of the Union, including Horizon Europe. The wish is to reach the final decisions by 2019, so to have enough time to prepare new actions in time before the switch off of Horizon 2020.

According to the Commission’s proposal, Horizon Europe shall also see the simplification of rules governing the access to European funds, so to lower administrative barriers that participants have to face for the management of research projects and improve their legal certainty. Special tools are also expected to be available to support member States still lagging behind in their development.
The new FP9 programme has been built by the European Commission on the basis of the interim evaluation of Horizon 2020 and the indications expressed by the high level group lead by Pascal Lamy. This working group, in particular, expressed the need to make the value of investments in R&I more easily understandable to all European citizens. The challenge has been accepted by the Commission, that worked to improve the definition of clear targets for Horizon Europe and their expected impact on global challenges.

An open approach to sustain competitiveness

The roadmap for European innovation has been already marked in 2013 with the adoption of Horizon 2020. The new FP9 will continue along this road in order to consolidate current results. The new programme shall be based on three pillars, with the central goal of strengthening the European research area through the sharing of excellence and the enhancing of the R&I system.
The first, fundamental pillar to reach these ambitious objectives is Open Science: according to the Commission, sharing of knowledge and free access to publications, data and management plans for research data should help to maximise the return on investment made under the new FP9 2021-2027 and improve the corresponding potential of innovation.
The European Research Council (ERC) should become, according to the Commission, the only referent for the development of high potential (and high risk) innovative ideas, from the lab to the market. Startups and SMEs shall find the support of two new tools specifically designed, respectively, to sustain early development and product commercialisation. Partnerships and collaborations within other European programmes shall be also available to boost interactions and collaborations among all stakeholders, from academia to industry, from civil society to investment partners.
The total budget for the Open Science pillar of FP9 should be approx. € 25.8 billion, the great majority of which (€16.6 billion) should be allocated to the ERC, that would become the tool available to researchers to directly define and manage the most innovative research. Some other € 6.8 billion shall support fellowships and movements of researchers under the Marie Skłodowska-Curie Actions. Infrastructural investments are also planned within the first pillar.

Global challenges and Open Innovation

The second pillar of Horizon Europe is “Global Challenges and Industrial Competiveness”, including all actions needed to support the current evolution of society and competitiveness of the European industry. The anticipated total budget (€ 52.7 billion) shall be used to support actions on the five different clusters identified by the new programme, i.e. health, inclusive and secure society, digital and industry, climate, energy and mobility, food and natural resources. A minor part of the funds (€ 2.2 billion) will support activities of the Joint Research Centre (JRC), the European institution providing technical support and expertise to the European Commission.
Open Innovation is the third pillar of Horizon Europe, under which € 13.5 billion shall be available to boost the creation of a true European innovation system. To reach this ambitious target, two other tools are planned to be available: the European Innovation Council (EIC, € 10 billion) and the European Institute of Innovation and Technology (EIT, € 3 billion). According to the Commission, member States should also see the doubling of available resources to support national initiatives within the more general context of “sharing excellence”.

A mission-oriented approach will be the key for success

Horizon Europe shall be based on the so-called “mission oriented” approach, under which R&I missions will focus on the actual needs directly coming from the civil society. According to the Commission, citizens should have an active role in their definition; this approach should also allow respecting planned timelines to reach the research targets established by the funded projects.
The preliminary missions identified by the Commission have been subject to a public consultation in early 2018; those final results are not yet available. The Commission published on its website a preliminary summary of the almost 1.200 answers received to the consultation, according to which all criteria proposed to identify the missions are important, with a particular attention to ambitious, but realistic, R&I actions (88% of respondents).
Other important criteria are a robust and social relevance of the missions (83%), the definition of clear lines of action, that can be defined and measured in time (78%), the possibility to develop multiple, bottom-up actions (78%) and cross-disciplinary and cross-sectorial actions involving all stakeholders (71%).
Horizon Europe’s R&I missions are also expected to be flexible (88%) and based on a pro-active management focused on the improvement of in-house competences. The measurement of the impact of the missions should be based on clear objectives and milestones (80%), and see the involvement also of national and regional stakeholder (75%). The majority of respondents (68%) agreed on the consultation of European citizens on the targets established for the missions.

The reactions of the pharmaceutical community

The European Federation of Pharmaceutical Industry Associations (EFPIA) expressed from its website a positive opinion on the proposal of the new research framework programme.
Research and development is an essential part not only of the European economic growth, but also of the competitiveness of the pharmaceutical sector, said EFPIA. Integrated and more personalised healthcare solutions and a vibrant and connected pan-European health and research ecosystem are the targets the pharmaceutical community is currently pursuing, and that may find new strength from the missions that will be activated under Horizon Europe, specifically within the Health cluster in the Global Challenges pillar.
“More than ever, the overall structure and ambition of Horizon Europe is centred on relevance and on impact for patients and society and places as much emphasis on fundamental as on translational research and close to market activities. This will require stepping up collaboration models between all stakeholders and all sectors (industries, technologies, public and private); the proposal for European Partnerships is therefore particularly welcome”, writes EFPIA in its statement.
The Federation would also support the call for an additional increase of the budget of the programme requested by the High Level Group on maximising impact of EU Research and Innovation Programmes. EFPIA recalled the positive results obtained by the Innovative Medicines Initiative Public Private Partnership under the Horizon 2020 framework, and the importance to facilitate translation of science and innovation into new health solutions.

Italy: The main themes discussed at the annual AFI Symposium

Focus on EU’s Countries

Giuliana Miglierini

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19 July 2018

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Italy: The main themes discussed at the annual AFI Symposium

More than 1,400 participants attended the 58° AFI Symposium, which took place on 6-8 June in Rimini (IT). The annual meeting organised by AFI – Associazione Farmaceutici Industria is the leading event in Italy for professionals working in the pharmaceutical industry; this year the discussions focused on the theme “The in progress transformations of the pharmaceutical industry in the digital era”.

An opportunity for contacts and discussions

The Symposium was supported by the official recognition of the Italian Drug Agency AIFA, and saw the participation of a wide panel of Italian and international experts and exhibitors. Many international associations of the pharmaceutical and biotech sectors were also present in Rimini, as well as representatives of some trade professional associations offering representation booths. EIPG was represented at the Symposium by its president Claude Farrugia and vice-presidents Piero Iamartino and Maurizio Battistini.
The three days hosted 13 different scientific sessions, those contents were defined with the contribution of AFTI (the Pharmaceutical Association of Ticino/Switzerland) and the Controlled Release Society, Italian Chapter. Many qualified speakers invited to give their presentations during the sessions are members of AFI’s working groups, thus having the opportunity to present the results of their work to the wider public of professionals. The Symposium offered also open access to students in Pharmaceutical Sciences, in order to support the formation of a profound industrial culture.
The annual meeting in Rimini is a traditional place for the Italian pharmaceutical community to establish contacts and start partnerships and collaborations; the exhibition area hosted this year 117 exhibitors, mainly promoting services and materials for pharmaceutical industry.

Two particular “corners” have also been active for the duration of the Symposium, the first one specifically focused on start-ups: an important opportunity to present new companies and their projects. The second corner was dedicated to students from universities: here AFI members gave a series of short talks about the professional requirements which are currently expected by the industry, in order to support students in better understanding and familiarising with their possible future, “real life” working environment typical of the pharmaceutical industry.

The main points of the plenary debate

The plenary debate saw the participation of the representatives of the Italian pharmaceutical and biotech industry and of AIFA to address how the future governance of the Italian pharmaceutical expenditure might be structured according to an industrial point of view (you can find here more details).
Costs and revenues should be taken into account to design the new, sustainable model of governance, according to the president of the Italian Association of the Pharmaceutical Industry (Farmindustria), Massimo Scaccabarozzi. Italy increased 20% its pharmaceutical production in the last eight years, mainly for export (77%) and currently ranks second in Europe after Germany, for a total value of € 31 billion. The Contract Development and Manufacturing (CDMO) sector is particularly developed in Italy, and currently ranks first in Europe for a total value of € 1,7 billion. Revenues for this sector increased 40% between 2010 and 2016, with a peak of 48% for high tech products such as injectables and biologics. If times are good for producers of branded medicinal products, the Italian industry of generics is still trying to conquer more space in the European market, explained the president of the generics association Assogenerici, Enrique Häusermann.
As for costs, the Italian public pharmaceutical expenditure amounted to € 19 billion in 2017. A big debate is currently undergoing in Italy on how to modify the current model to adapt the more that 7,000 new molecules expected to reach the markets in next years. The position emerged from the Symposium sees the medicinal products as being part of a more complex pathway of cure, and no more a single player.

A wide range of topics for the scientific sessions

All industrial areas have been addressed during the scientific sessions, with a special attention on current issues and innovative solutions. The session on active pharmaceutical ingredients has been moderated by Piero Iamartino on behalf of AFI and Maurizio Battistini and behalf of AFTI. The session discussed the issue of data integrity during GMP inspections of APIs suppliers, and the impact of the implementation of GDP. Other contributions addressed the development of a standardised extract of Cannabis Sativa and its regulatory requirements, and the increasingly important role played by excipients on the final quality of medicinal products. Compliance to GMP requirements for excipients may be achieved through the adhesion to the EXCiPACT certification framework developed by International Pharmaceutical Excipients Council Europe (IPEC). According to AFI’s working group on excipients, suppliers of excipients are often giving priority to other fields of application, such as cosmetics and food, as a result of the more interesting economic value of the business. A better dialogue to compare quality requirements under different certification schemes (e.g. HACCP for food) is thus important to improve the quality compliance of excipients supplies for the pharmaceutical market.
The Pharmaceutical Technology session addressed the theme of paediatric formulations, that still lacks a common set of internationally recognised guidelines. Another main issue is how to determine bioequivalence in the development of generics for paediatric use and the selection of the correct dosage for each age segment. Issues are also present as for the design of paediatric clinical trials.
Among analytical techniques to support GMP requirements, the recent revision of Annex 1 for the production of sterile products indicates microbiological and particle counting as one of the main topics deserving attention. Contamination of biologicals has been also discussed, as well as the possible contamination with chemical substances, for example during cleaning.
Serialisation and Industry 4.0 have been central to the debate on innovation in pharmaceutical production, together with digital innovation, data management and automation (MES, manufacturing execution systems). Quality-by-design is the new paradigm for the sector, and offers the opportunity for a more structured and scientific approach to production.
During the session on Regulatory Affairs the new AIFA’s position paper on biosimilars has been presented, supporting the full possibility of exchange of an originator with the corresponding biosimilar product. This even if a biosimilar is not the “exact” generic copy of the originator, because of the complexity of the biological systems and of the formulation. According to AIFA’s representative, the choice on interchangeability remains in any case upon the medical doctor prescribing the therapy.
Special productions targeted to a single, specific patient have been also discussed from the regulatory point of view, and include allergens, medicinal gases, homeopathic products, radiopharmaceutics and herbal medicines.
As for clinical studies, the current situation of phase 1 trials in Italy has been discussed. The AIFA’s central Coordination center of Ethical Committees has been established in April 2018, and it will be responsible to monitor the execution times for authorisation requests by the single committees and the uniformity in the application of the relative rules. The final, executive decrees governing the committees (decreased in number from 100 to 40) is soon expected to be published. Digital transformation and use of artificial intelligence in clinical development have been also discussed.
Drug delivery for immunotherapy has been the focus of the session dedicated to R&D, with a special attention to oncology applications. Innovative systems, such as RNA-lipoplexes and nanoparticle systems, offer many opportunities to develop new and efficient therapeutic approaches.
In the field of rare disease, the recent experience of the Bambino Gesù Hospital in Rome in the development of the first Italian CAR-T cell therapy has been exposed. The potentiality of gene therapy and microbiome have been also discussed.
The results in the AIFA’s inspection activity with respect to pharmacovigilance have been addressed in the light of the activation of the new European EudraVigilance network. The pharmacovigilance session also debated the theme of vaccines and their impact on vigilance post-marketing activities.
The new European regulation on medical devices that will entry into force in 2020 and the new requirements introduced thereof have been debated during the session dedicated to medical technologies.

UK invests in industrial biotechnologies, innovation and talents

Politics & Business

Giuliana Miglierini

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19 July 2018

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UK invests in industrial biotechnologies, innovation and talents

The new “Industrial Biotechnology Strategy to 2030” is just one of the many new initiatives recently announced in UK in the field of biotechnology and innovation, with the more general target to increase the competitiveness of the country on the global scenario. A new R&D innovation center for the manufacturing of small molecules will be built in Scotland, while the creation of innovative bioscience companies will be supported by the new £ 2.5 billion British Patient Capital fund launched by the British Business Bank. Finally, UK government announced a £ 1.3 billion investment to attract and retain world-class talents as a fundamental part of its Industrial Strategy.

The National Industrial Biotechnology Strategy to 2030

Industrial biotechnology (IB) is central for the production of innovative biopharmaceutics as well as many other products in different industrial sectors. From green fuels and other energy resources to waste recycle, plastic’s production and detergents – just to make few examples – industrial biotechnologies represents a fundamental approach for the handing of bioeconomy and clean manufacturing and provide a more sustainable and eco-friendly business model. According to the Strategy – launched by the Industrial Biotechnology Leadership Forum (IBLF) in partnership with the UK BioIndustry Association (BIA) and the two collaborative networks in industrial biotech, CBMNet and BIOCATNET – industrial biotechnologies offer a disruptive potential of more than $ 34 billion on the UK market.

High value chemicals and recombinant biologics represents some examples of high growth areas of application; synthetic biology also offers great opportunities to create new medicines, green chemicals and fuels. According to the report, the proportion of chemicals produced by biotechnology is expected to increase significantly by 2030, especially in the field speciality chemicals. SMEs are expected to play a major role in the development of the UK’s innovation potential in the field of industrial biotechnologies.

The Industrial Biotechnology Strategy will be implemented in three consecutive phases, with actions spanning across seven themes starting from the achievement of a wide external consensus on a consistent long-term policy landscape supporting industrial biotech. This first, essential step shall couple with the availability of a supportive financial environment that recognises the potential of IB as a driver of growth and innovation. The Strategy aims to make industrial biotechnology a major contributor to clean economic growth across all UK’s regions by investing in infrastructure and regional footprint. The final goal is to position UK as a global hub for industrial biotechnologies, their innovation and commercialisation. This also requires the availability of a robust regulatory framework to support the development of new products and technology according to the “risk aware innovation” approach. High skills are also required to achieve the goal, thus improving the attractiveness of the country for specialised workforce. Finally, just one IB community voice should be promoted in order to provide consistent and clear messages to the society on actions undertaken in this increasingly strategic field of UK’s economy. “The Strategy describes the vision of the UK industrial biotech community, driven by the IBLF; in harnessing the world-class science we have in the UK in order to enable industrial biotech to become a mainstream part of UK industry”, said Steve Bagshaw, CEO of Fujifilm Diosynth Biotechnologies and Chair of the IBLF.

The biopharmaceuticals (biologics) sector represents a well established example of good practice for UK industrial biotech, on the basis of a wide and efficient network of academic-industrial collaborations (e.g. BioProNET) sustained by national funding and infrastructure to support innovation (e.g. the High Value Manufacturing Catapult).
The Strategy also recalls the numbers of the market for biopharmaceuticals, that in 2016 saw seven of the top ten drugs by sales, and eleven of the top 20 belonging to this category of medicinal products. This market is expected to grow at a compounded average growth rate of 8.5% in the period 2016-2024. “The lessons of this sector can be applied more broadly to leapfrog into other emerging sectors”, states the document published by IBLF. Industrial biotechnologies also address at least six of of 17 Sustainable Development Goals established in 2015 by the United Nations.

Industrial biotechnologies are very important, for example, to develop new therapeutic approaches based on the use of microbiome; since 2010, reports the document, microbiome specialists have raised over $ 1.8 billion investments. While more than 95% of the microbiome remains undiscovered, IB may play an important role in the identification and characterisation of bacterial strains and in the elucidation of their functions, also at the genetic level.
To reach its final goal, the IBLF report considers the current UK industrial biotech landscape and recent analyses run by the government, academic and industrial point of view, the IB investment and commercialisation reference framework and how IB activity in the country compares with foreign competitors. The Strategy also provides short- and long-term recommendations to support IB and UK global competitiveness, based on a coordinated approach among all stakeholders. According to the report, there is a great potential for further expansion in coming years of the current 14,000 full-time jobs, with a great impact also in regions such as the North of England. Another main result expected by the new Strategy is represented by IB impact on the reduction of carbon emissions, thus answering the challenges posed by climate change. The UK currently produces the second highest volume of CO2 of any European country, according to the document.

A new R&D innovation centre in Scotland

The new Medicines Manufacturing Innovation Centre (MMIC) is one of the early projects to receive funding from the UK’s Industrial Strategy Challenge Fund. The new facility will be built in Renfrewshire, Scotland, for a total investments of £ 56 million, made available by a pool of partners among which are Scottish Enterprise (£ 15 million), UK Research and Innovation, through Innovate UK (£ 13 million), GSK and AstraZeneca (£ 7 million each).

The MMIC will focus on the manufacturing of small molecules, with the goal to capture a bigger slice of the global £ 98 billion small molecule pharma and fine chemical market. The centre will make available to companies the full range of manufacturing technologies – primary, secondary and high value – so to improve the transformational process to adapt already existing productions to new, more efficient methods.
The new facility will be located within the Scotland’s Advanced Manufacturing Innovation District, close to the National Manufacturing Institute for Scotland (NMIS). According to the Association of the British Pharmaceutical Industry (ABPI), the new centre should host at least 80 highly skilled R&D jobs by 2023 and attract over £ 80 million investment by 2028. Researchers will be able to work side by side with academics and manufacturing partners to design new ways for the future development of medicines and in to the supply chain.
“Medicines manufacturing is no longer the siloed, labour intensive process of yesteryear. This is a strong signal of intent from Government and the pharmaceutical industry that they are ready to get behind the UK as a global leader in medicines manufacturing”, said ABPI’s chief executive Mike Thompson.

New funds to attract the best talents

The attractiveness of UK for international best talents in science and innovation is also central to government’s new investment (for a total of £ 1.3 billion) announced by Business Secretary Greg Clark. The new UK Research and Innovation (UKRI) Future Leaders Fellowship Scheme (see here the announcement) may count on a £ 900 million budget over the next eleven years to fund at least 550 new fellowships for researchers from around the world.
As explained by Mr Clark during the International Business Festival in Liverpool, the investment will support British universities and businesses to train the next generation of entrepreneurs, innovators and scientific leaders. An action being essential for the future competitiveness of UK in the post-Brexit era. According to the government, the new fund will help ensure the UK invests 2.4% of GDP in R&D by 2027, so to become the most innovative economy by 2030. The UKRI Future Leaders Fellowship Scheme will support six funding competitions and provide up to seven years of funding for early-career researchers and innovators, including support for part-time awards and career-breaks, and for the first time it will be open also to businesses.
Some other £ 350 million will be available to collectively fund prestigious fellowships schemes from the Royal Society, the Royal Academy of Engineering, the British Academy and the Academy of Medical Sciences. Other £ 50 million over the next five years has been also allocated through the National Productivity Investment Fund for additional PhDs, including 100 PhDs to support research into artificial intelligence.

A new fund for innovative bioscience companies

The new British Patient Capital (BPC) is a £ 2.5 billion fund created by the British Business Bank in order to provide long-term funding for high growth potential companies in innovative bioscience and other sectors. The BPC will be developed as a separate subsidiary of the British Business Bank.

The creation of the fund has been welcomed by BIA’s CEO Steve Bates, as recognition of the request from the BioIndustry Association for more ambitious public investment. “British Patient Capital can cornerstone the next generation of UK life science companies to scale to global leadership. The need to increase in scale up capital in life sciences was explicitly recognised in the Government’s Life Sciences Sector Deal and the Treasury’s Patient Capital review”, said Mr Bates.

The new fund sees Russ Cummings as one of the non executive directors. He was the former CEO of Touchstone Innovations, one of the UK’s leading technology investment. Anne Glover is the other non executive director, previously CBE, CEO and co-founder of Amadeus Capital, member of the Council for Science and Technology, and former chairman of the BVCA and Invest Europe.
The fund includes a diverse range of strategic investors, such as charity, pharma, public and private investors. British Patient Capital will invest in venture capital funds, which in turn will be responsible for the selection of companies eligible to receive funds. The Dementia Discovery Fund (DDF) is one of the two VCs already selected to receive first investment under the new BPC; the other initial recipient is venture capital firm Draper Esprit.

Giuliana Miglierini

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The National Industrial Biotechnology Strategy to 2030

A new R&D innovation centre in Scotland

New funds to attract the best talents

A new fund for innovative bioscience companies

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