Home Authors Posts by Giuliana Miglierini

Giuliana Miglierini

208 POSTS 0 COMMENTS

The importance of early interactions between regulators and pharma industry

Giuliana Miglierini
-
0
The importance of early interactions between regulators and pharma industry

The evolution towards new digital models to run clinical R&D requires all stakeholders, including the pharmaceutical industry, clinical centres and regulators, to optimise their interactions in order to streamline from the beginning the optimal planning of all activities. EMA recently published two scientific articles addressing different aspects of early interaction, with the aim to improve evidence generation and speed up the approval process. The Agency also released an updated version of the Q&A document “Qualification of digital technology-based methodologies to support approval of medicinal products”.

The importance of post-approval evidence generation

Real-word data (RWD) coming from the post-approval use of a new medical product are very important to assess its performance and safety in the general population. Post-licencing evidence generation (PLEG) is discussed in the article published in the British Journal of Clinical Pharmacology, under the perspective of early advice activation to optimise PLEG plans, which need to be submitted to EMA together with the marketing authorisation application (MAA).

Post-approval RWD should be generated in a reasonable, not too long time length, as they are used to inform decisions by both the regulatory authorities (also in the US and Japan) and the value proposition evaluation run by health technology assessment (HTA) bodies. Despite the availability of various scientific advice tools, this instrument is not yet broadly used by Marketing Authorisation Holders (MAHs) for the planning  of their PLEG activities. These are utmost important to clarify the uncertainties left behind from the pre-approval development, as they may help identifying emerging points requiring attention. PLEG data come not only by new trials (randomised or not, observational, interventional, pragmatic, etc), but also from electronic healthcare records and other medico-administrative documentation, as well as from smart devices (wearables, smartphones, etc.). 

Post-authorisation safety studies (PASS) or post-authorisation safety efficacy studies (PAES) are possible examples of PLEG requests coming from the regulators; MAHs are free to develop their own initiatives, including the use of data from temporary authorisation of use programmes or early access to medicines schemes.

The article provides a discussion of the rationale for PLEG studies according to the perspective typical of the different stakeholders, i.e. regulatory authorities, HTA bodies or National Immunisation Technical Advisory Groups (NITAGs) for vaccines. Evidence sufficient to determine the risk–benefit profile has to be available to reach approval, for example; this evidence can be then complemented with PLEG data, according to an impact-based hierarchic approach led by post-approval data specifically requested in order to confirm efficacy and safety (e.g. in the case of conditional or exceptional marketing authorisations). 

The evidence acquired by EMA in the period 2012-2016 shows that data from phase 2/3 studies are mainly related to conditional MAs’ PLEGs requests, while evidence on long-term real-world safety and efficacy and disease epidemiology more relates to exceptional circumstances authorisations. The resulting evidence was included in the product information in 72% of requests reaching the fixed milestones. “Notably, all conditionally authorised products had imposed obligations to collect additional data of between 1 and 4 activities”, write the authors. Analysis of centrally approved products in the period 2005–2013 shows the use of a registry has been imposed by EMA in 4% of non orphan and 29% of orphan medicinal products, and in 12% of conditional MAs and 67% of exceptional circumstances approvals, respectively. The primary objective of such registries was to track safety data (53% of cases). 

Several forms of early advice are available and are discussed in the paper, with the possibility to activate actions with single regulators or, for example, in parallel between regulatory and HTA bodies, or EU-US bodies. The potential benefit for patients is the main criteria the EUnetHTA Early Dialogue Working Party uses to select products for consolidated parallel consultations. Sharing of best practices, qualification of data sources and methods and monitoring of PLEG’s impact in different geographic regions are among EMA’s suggestions to correctly approach these procedures. 

How to support the use of digital technologies

Digitalisation is a reality in the way clinical studies are being conducted; for example, it plays an essential role in the generation of RWD or in the continuous monitoring of pato-physiological parameters. The second paper from EMA was published in Nature Reviews Drug Discovery and addresses how the Agency could support the development of reliable digital tools, able to provide data characterised by a quality level sufficient to meet regulatory needs. This tools can be classified under the regulatory point of view as medical devices or medicinal products depending from their principal mode of action (alone or in combination with a medicine)

EMA has recently activated a new voluntary procedure for the qualification of novel methodologies, which can be used to establish their regulatory acceptability. The experience gained so far suggests developers to seek early advice, so to optimise the use of digital technologies with respect to the goals established in the benefit-risk evaluation. EMA, on its side, can better and timely set the multidisciplinary team needed to assess the technologies and their outputs, identifying the optimal interaction channel and guiding the development targets for data generation and acquisition. 

Early tests aimed to gain proof-of-concept on the applicability of a certain digital technology should be followed by a validation phase aimed to gain pivotal data to be used in the marketing authorisation application (MAA). 

All questions for advice on the digital technology posed to EMA should fall within the Agency’s remit, suggests the article. In particular, the expected benefits compared to traditional methods should be clearly explained, together with the interest, contest of use and identification of a clinically meaningful change. Developers should document the reliability, accuracy and repeatability of the technology, according to principles of design control and medical device regulations. Just high-level information is requested in relation to technical parameters that do not impact on the assessment of the benefit-risk ratio for the medicinal product. 

The MAA should also contain a risk assessment of the impact any changes introduced to the final digital technology element during development would exert on the validity of the generated clinical data; this exercise should be run according to ICH guidelines Q8, Q9, Q10 and Q12. Whenever applicable, digital technologies have to fulfil relevant legislations for medical devices and in vitro diagnostic, as well as the the GDPR regulation on the protection of personal data. CE marks for medical devices are not needed during development, but are necessary at the time of marketing. 

New market opportunities in the post-pandemic era

Giuliana Miglierini
-
0
New market opportunities in the post-pandemic era

The Covid-19 pandemic turned out to completely redesign many activities and markets all around the world. Pharmaceutics and healthcare services have been greatly impacted by the emergency, which boosted the transition towards new models of interaction between healthcare professionals (HCPs) and patients on one side, and the industry and HCPs on the other. A series of reports from IQVIA analysed the different aspects of this transition, as well as the markets’ dynamics during the pandemic.

The impact on the pharmaceutical industry

Some 8,1 million Covid-19 confirmed cases worldwide are recorded while we are writing, with 440.290 deaths (5,5%, WHO data, updated to 17 June 2020). The Covid-19 pandemic seriously impacted the global pharmaceutical product supply chain, affecting both active ingredients, excipients, finished products, logistics, shipping. Multiple origin and destination countries adopted different restrictions and measures against Covid-19 that directly or indirectly had an impact on freight movements.

China was the first country dealing with the new coronavirus in February 2020; about a half (49.3%) of the manufacturing activities in the Hubei province has already reopened as for the end of April, according to IQVIA, and the pharmaceutical sector has recovered 70% of its original capacity. This is of great importance with respect to the regular production of pharmaceutical active ingredients and excipients to be exported in Western countries. Procurement of raw materials greatly suffered in March and April, leading to medicines shortages in many European countries. The problem was also exacerbated by the stockpiling dynamics many chronic patients put in place in the first phase of the lockdown to be sure they had enough of the medicines they need.

Trends in the EU and US pharmaceutical market

Prescription and OTC medicinal products showed a completely different performance in the 5 top EU countries during the pandemic, says IQVIA. Prescription products were characterised by sales decrease, more prominent in Italy (-4.4%) and France (-4.0%), with the exception of some therapeutic classes (antineoplastic and immunomodulating agents ATC L class, nervous system ATC N class) that showed an increase in volume sales in most countries.
On the other hand, OTC products showed a positive performance in all countries apart Germany (-1.7%), with the best results obtained in France (+7.1%) and UK (+5.7%). 

A similar trend was observed in the US (see here and here), where the FDA started a collaboration with Aetion to analyse real-world data on the use of Covid-related diagnostics and therapeutics. The FDA also simplified rules on digital therapeutics (DTx), in particular to assist treatment of Covid-related psychological distress. DTx may represent an increasingly useful therapeutic option to treat many conditions in the future digital e-health scenario.

The impact on new launches and clinical trials

The prioritisation of manufacturing activities towards medicines needed to fight the pandemic slowed down many R&D projects; many launches of new products had to be postponed. IQVIA estimates a $ 10 billion underperformance for years 2020-2028, resulting from the impact on the 109 new medicines launched 2018-2019, the 50 products ready for launch in 2020 and the more than 340 planned to reach market by 2028. A complete rethinking of the planning and modalities of these activities is envisaged, pointing towards virtual launches with engagement of opinion-leaders and integration of omnichannel marketing with telehealth data. 

Hospitals were almost completely devoted to Covid-19 patients during the last few months, and 88% of them in the Europe, Middle East, and Africa (EMEA) region did not allowed Clinical Research Associate (CRA) visits during the emergency phase. As a consequence, new virtual modalities to interact with clinical centres had been put in place, both to initiate a site and for remote monitoring. Experimental protocols had been simplified to remove critical activities, moving to electronic patient reported outcomes (eCOA) and promoting telemedicine to keep in touch with patients staying at home

Digital promotional activities and healthcare services

The lockdown almost halted sales forces’ face-to-face visits to medical doctors and HCPs in many countries. E-meetings, e-detailing and other remote methods (phone, postal, e-mailing) have emerged as alternatives to maintain the interaction active, especially in the most hit countries (China, South Korea and Italy). This shift required rapid training of sales forces. According to IQVIA, the new KPIs include 4 remote calls per Representative (Rep) and per day as an average, approx. 14 minutes duration each. 

The lockdown and the consequent request to retain social distancing while resuming normal activities acted as a main driver for remote interactions between medical doctors and their patients. Digitalisation is due to become the “new normal”, as planned in many roadmaps approved by governments and institutions all over the globe. The transition process is not so simple to achieve and it may present some risks, as many patients would still prefer face-to-face interaction with their doctors, thus postponing diagnostic testing and therapy initiation. 

According to IQVIA, an >1500% increase in telehealth claims from pre-Covid baseline has been observed, requiring for future improved attention to patients’ journey, identification of alternative sites of care for therapy administration and rethinking of physicians’ targeting and segmentation. Remote monitoring may support the follow-up of less severe Covid patients, limiting the risk of exposure of the general population. Call centres have also been activated for patients to directly call into manufacturers to ask product enquiries, while their doctors were assigned to Covid-related activities.

Looking for the solution against Covid-19

Giuliana Miglierini
-
0
Looking for the solution against Covid-19

Researchers all over the world are looking to new therapeutic options for treatment or prevention or the Covid-19 epidemic. Not only looking at human medicines: many activities are ongoing also in the veterinary sector, where a new guidance has been issued by the EU  Commission, EMA and the Coordination Group for Mutual Recognition and Decentralised Procedure – Veterinary (CMDv) to illustrate the possible flexibilities in the development, manufacturing and distribution of veterinary medicines during the emergency (see also the article in the Regulatory section of this newsletter to know what EMA is doing to facilitate pharmaceutical companies, as many indications are similar for the human and veterinary sector). We provide some news about recent advancements, both for medicinal products and vaccines.

Looking for genetic risk factors

Precision Life, a UK company specialised in the use of artificial intelligence (AI) to analyse patients’ genomic and clinical data, published on its website the results of a study on Covid-19 patients aimed to identify genes potentially related to the sepsis associated to the disease. The study was based on a combinatorial association approach to analyse a sepsis population derived from UK Biobank, and led to the identification of 70 sepsis risk-associated genes, potentially related to the mechanisms underlying sepsis pathogenesis in severe Covid-19.

Several possible targets for a future therapy have been also identified, including endothelial cell dysfunction, PI3K/mTOR pathway signaling, immune response regulation, aberrant GABA and neurogenic signaling. The study also looked for medicines that might be repurposed to meet these targets, ending up in 59 possible candidates against 13 different sepsis risk genes. The selected active chemical compounds are all included in the DrugBank or ChEMBL databases. 

India is working on repurposing 

The protocol to use lopinavir/ritonavir combination therapy amongst symptomatic acute Covid-19 patients is just one example of the work the Indian Council of Medical Research (ICMR) is doing to identify already approved medicines that may turn useful to fight the virus (see more on the Times of India). The lopinavir/ritonavir combination was initially authorised to treat HIV infections, and then also used during the SARS and MERS coronavirus epidemics. Also disulfiram was already used in these instances, as it can promote the immune response; the drug was originally developed to fight alcohol dependence through the production of nausea and other unpleasant symptoms in contact with the alcohol. Loperamide is under study in India to treat Covid-19’s diarrhoea symptomatic manifestations. Among other medicinal products under investigation are the anti-inflammatory against psoriasis itolizumab and the immunomodulator tocilizumab, this last being widely used during the emergency also in Western countries. Immunomodulation is also the target of mycobacterium-w, a drug to treat leprosy which already proved useful in severe blood infections. 

FDA approved remdesivir for emergency use

On May 1st, the US Food and Drug Administration (FDA) issued an Emergency Use Authorisation (EUA) relative to Gilead’s anti-HIV remdesivir, on the base of a study showing the drug could cut of 31% recovery times for Covid-19 patients compared to placebo (see more on FiercePharma). The authorisation states that “based on the totality of scientific evidence available to FDA, it is reasonable to believe that remdesivir may be effective in treating Covid-19” if used under the prescribed conditions, and that “there is no adequate, approved, and available alternative to the emergency use of remdesivir for the treatment of Covid-19”.

The terms of the EUA establish that the drug can be supplied only to authorised distributors or directly to a US government agency, can be administered by IV infusion to treat patients with severe disease (SpO2 ≤ 94% on room air, requiring supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation) at dosing regimens detailed in the authorised Facts Sheets. A Fact Sheet for patients and parents/caregivers has been also issued by the FDA.

The Agency also approved under EUA the use of the anti-malaria drugs hydroxychloroquine and chloroquine. Some 30 million doses of hydroxychloroquine sulfate were donated to the U.S. Department of Health and Human Services (HHS) by Sandoz, plus another million doses of Resochin (medical grade chloroquine phosphate) donated by Bayer Pharmaceuticals. The FDA also released a note to warn against the possible severe side effects of hydroxychloroquine, and the need of medical supervision for its administration.

Hyperimmune plasma and LMW heparins

The plasma of people that won the Covid-19 infection is rich of gammaglobulins, and it may be administered to patients to sustain their immune response. This hypothesis has been supported by analysts, as reported by FiercePharma, and it is under testing in Italy after a first successful experimentation in the Mantua and Pavia hospitals. 

The Italian Medicines Agency AIFA also authorised the off-label use of low molecular weight heparins, for the prevention of venous thromboembolism in the first phase of the disease and for the control of the severe thromboembolitic phenomena resulting from the advanced, hyper-inflammation phase of Covid-19.

Dr. Anthony Fauci, the head of the medical task force supporting the Trump administration in dealing with the pandemic, during a recent hearing at the US Senate commented the possibility for children to be back to school saying that “the idea of having treatments available, or a vaccine, that facilitate the re-entry of students into the fall term would it be something a bridge a bit too far. The drug that has shown some degree of efficacy, was modest, and was into hospitalised patients. […] Probably, the thing that would be closest to utilisation would likely be passive transfer of convalescents’ serum”, referred to the possibility to make a preventive immunisation to increase the safety of the students (see the video of the hearing, from min 58.22)

The difficult search for a vaccine

Many are the candidate vaccines under development worldwide (see the official WHO list), and it is difficult to guess who will be the winner. During the hearing at the Senate, the same Dr Fauci remarked there are some points of consideration applicable to the development of all vaccines.

“First of all – he said –, there is no guarantee that the vaccine is actually going to be effective. You can have everything you think that’s in place and you don’t induce this kind of immune response that turns out to be protective and durably protective. So, one of the big unknowns is will it be effective? Given the way the body responds to viruses of this type, I’m cautiously optimistic that we will with one of the candidates get an efficacy signal. The other thing that is unknown, that’s of concern, but we will be able to go around this doing the testing properly, is that you do getting an enhancement. Namely, there were a number of vaccines, two in particular. […] The vaccines induce a sub-optimal response, and when the person gets exposed, they actually have an enhanced pathogenesis of the disease, which is always worrisome. So we want to make sure that that doesn’t happen. Those are the two major unknowns. Putting these two things together, we are cautiously optimistic that we will have a candidate that will have some degree of efficacy, hopefully, a percentage enough that will induce the kind of herd immunity that would give protection to the population at home.”  (see the video from min. 1.26.36)

The World Health Organisation released at the end of April a guidance document on the prioritisation of vaccines, stating that “should a vaccine’s profile be sufficiently superior to the critical characteristics under one or more categories, this may outweigh failure to meet another specific critical characteristic”. The WHO also advised companies working to the task that vaccines which would not meet multiple critical characteristics under the proposed criteria are unlikely to pass the assessment process. The criteria address candidate vaccines under different perspectives, assigning a certain amount of points to each item in order to obtain a prioritisation list. For each attribute it is provided the minimal acceptable profile to be met and the criteria to be used for assessment.

Many techniques under evaluation

The complexity and difficulties to be faced to obtain a truly useful and safe vaccine have been discussed by Derek Lowe in a commentary published in Science Translational Medicine. The problem is being addresses using many different techniques for vaccine development, some quite old and well established, other very new and still characterised by many question marks.

A starting point to take into consideration is that the Sars-Cov-2 appears to be a rapidly mutating virus (see for example here and here), thus making more difficult the availability of a truly efficient vaccine; this is similar to what already occurs with the influenza vaccine, for example, with the circulating wild type virus often different from strains used to manufacture the seasonal shots. 

“Live attenuated virus” vaccines are viral particles that cause a real, but attenuated infection. This category is often the most efficient in generating a long-lasting immunity. According to Derek Lowe, the difficulty is represented by the fine tuning necessary not to generate a virus too “aggressive”, thus leading to the true disease, obtained by a lab process imitating the natural mutation that occurs during time upon co-existence of the virus and the human host. 

“Inactivated virus” vaccines utilise completely unfunctional virus obtained by exposition to high temperature or desaturating agents, i.e.formalin or beta-propiolactone. The immunisation procedure requires booster shots, as the efficiency of the vaccine is lower; reproducible manufacturing can also represent a challenge to be achieved. 

Some vaccines are based just on one protein or piece of protein of the virus, able to cause the immune response in the host. This make them easier to manufacture, since it is possible to use recombinant technology, but they often require the use of adjuvants to produce a sufficient immune response. Recombinant proteins can also be assembled to give a “virus-like particle”(VLP) to be used as vaccine. 

DNA vaccines are quite young, based on circular plasmids coding for the antigen protein. The technique is similar to those used in gene therapy: upon insertion in the host cells using viral vectors, the target protein is hereby directly produced. The advantage is that the final product presents less issues with protein folding or glyco-post-modifications. No human product of this type is yet available; they would suffer the same problem of stability of gene therapies, suggest Derek Lowe. 

mRNA vaccines are also a recent category, using messenger RNA instead of DNA. Here the issue is represented by the need to limit the innate immune response against the infection in favour of the adaptive one generating antibodies against the target protein. Should this not occur, the immunity would be just short term. An advantage is a reduced immune response against the vector, but again there is a problem of stability of the mRNA.

Derek Lowe also discusses the different adjuvant technologies, and the many open questions as for the need to cope the demonstration of efficacy with the very tight timelines to reach the approval of the first vaccines to be use in humans. Shortcuts are inevitable, he argues; for example the animal testing of the Moderna’s mRNA vaccine has been completely skipped. The definitions of the endpoints – surrogate or not – for clinical studies is another open issue, as it is the length of the immunity provided both from the human disease and candidate vaccines. “My guess is that we may end up with a first-round vaccine that doesn’t last as long as it might, but will provide enough immunity to do the job and provide cover for us to collect more data on an optimised candidate”, writes Lowe.

Last, but not least, the question of safety is not secondary, as severe adverse effects might occur upon administration of medicines – as also vaccines are – targeting the immune system. “But you can’t avoid the problem: the huge person-to-person variation in everyone’s immune system means that these severe events can never be ruled out at some low level if you’re dosing enough people”, he adds.

How the EU Commission and the European medicines regulatory network are handling the Covid-19 emergency

Giuliana Miglierini
-
0
How the EU Commission and the European medicines regulatory network are handling the Covid-19 emergency

A wide variety of initiatives have been implemented at various level of the European institutions in order to fight against the diffusion of the Sars-Cov-2 virus. Among these are the institution of the EMA pandemic Task Force Covid-ETF and the Q&A document providing guidance to stakeholders on adaptations to the regulatory framework to address the new challenges, jointly published by the EU Commission, EMA and the European medicines regulatory network. These three actors also agreed on measures to face the impact of the epidemic on the due schedule of inspections of manufacturing facilities or other sites relevant for medicinal products in the European Union.

The Covid-ETF Task Force

The European Medicines Agency announced at the end of March 2020 the composition and objectives of its new pandemic Task Force, Covid-ETF. The task force has been set up in accordance with EMA’s Health Threat Plan and it is acting in support to the European Commission and Member States to cope with the spread of the epidemic, namely on aspects related to the development, authorisation and safety monitoring of therapeutics and vaccines intended for the treatment or prevention of Covid-19. The complexity of the new disease required EMA to revise the composition and line of action of its ETF so to face new challenges in terms of identification of the potential or repurposed medicinal products which may prove useful for prophylaxis or treatment, and the coordination of clinical trials across Europe.

The Covid-ETF is run under the supervision of EMA’s CHMP Committee and is chaired by the Agency’s scientific lead for the Covid-19 pandemic. Members include the heads of the CHMP, Paediatric (PDCO) and Pharmacovigilance Risk Assessment (PRAC) Committees and those of several EMA’s working groups (SAWP, VWP, IDWP, BWP, QWP, SWP, BPWP, CMDh), plus two additional representatives from the Co-ordination group for Mutual recognition and Decentralised procedures – human (CMDh) of the Heads of Medicines Agencies, two members from the Clinical Trial Facilitation Group (CTFG), and the CHMP Rapporteur and Co-rapporteur for products intended for treatment or prevention of Covid- 19, as well as three CHMP peer reviewers across all products. Specific experts from the rapporteurs’/peer reviewers’ teams may also be appointed, as well as a representative from Reference Member State (RMS) for products in the context of mutual recognition/decentralised procedures. Meeting of the Covid-ETF Task Force can be attended also by EMA’s Executive Director and representatives from the European Commission. Experts from other working groups (GCP IWG, PhV IWG, GMDP IWG) and observers from the WHO, the European Centre for Disease Prevention and Control or the EDQM (or other regulatory authorities) can be invited whenever appropriate. 

The mandate assigned to the Task Force includes the reviewing of all scientific data on Covid-19 medicinal products, including those requested to pharmaceutical companies. Preliminary discussion may also start with the interested parties, and comments on development plans is possible when formal rapid scientific advice is not feasible. The Task Force also provides support to run clinical trials in the European Union, and contributes to product-related assessment acting as peer reviewer and as forum for discussion on the rolling data assessment. The PRAC Committee’s activities also benefit from the work of the Covid-ETF, which is in charge of providing scientific input to committees and working parties and to draft scientific positions and input to public communications. 

The guideline on medicines to treat Covid-19

A Notice to Guidance on expectations for medicinal products for human use during the Covid-19 pandemic has been released on April 10th in the form of a Q&A document. The guideline, jointly developed by the EU Commission, the Coordination group for Mutual recognition and Decentralised procedures – human (“CMDh”), the Inspectors Working Group and EMA, describes how the traditional regulatory framework has been adapted to face the challenge to rapidly and safely identify useful treatments and vaccines against the virus.

The document specifies the procedures to rapidly obtain a marketing authorisation (MA) in other European countries for an already approved medicinal product, or how to activate compassionate use for not yet approved ones. MA holders unable to fulfil the deadlines for authorisation renewal due to the pandemic are advised to contact the relevant authorities. MAHs can also request an exemption to the sunset clause in view of exceptional circumstances and on public health grounds, should the launch of new products had to be postponed due to the health emergency. 

A very hot issue during last months was represented by the difficulties to guarantee a steady flow of APIs and intermediates from China and India for the manufacturing of medicines in Europe. Question 2.1 addresses how to rapidly add a new manufacturing site for part or all of the manufacturing process, in order to reduce the risk of shortages or disruption of supply. The chosen tool is an Exceptional Change Management Process (ECMP), that MAHs can activate for crucial medicines for treatment of Covid-19 patients. ECMP allows MAHs to source starting materials, reagents, intermediates or active substances from suppliers not specifically mentioned in the marketing authorisation “if that is necessary to prevent/mitigate shortages of supplies in the EU”. The same applies to using manufacturing sites or sites responsible for quality control that are not specifically mentioned in the dossier.

Question 2.2 describes how to handle possible issues with GMP certificates, as international inspections have been blocked with the global lockdown. For manufacturing sites located within the European Economic Area (EEA), the validity of GMP certificates should be extended until the end of 2021 without need for further action. The same applies to extra-EEA sites, unless the issuing/supervisory authority takes any action that affects the validity of the certificate. Should an inspection be required, and in case of no operational mutual recognition agreement (MRA) or scope not covered by the MRA, a distant assessment by an EEA supervisory authority may be conducted. In this case, the certificate will indicate that it has been granted on the basis of a distant assessment. The guideline also indicates that the pre-approval or routine on-site inspections will resume as soon as restrictions are lifted, according to a risk-based planning taking into account the date of the last inspection. 

GDP certificates should also maintain validity up to the end of 2021 (Q 2.3), in this case too due to the current difficulties to run inspections of distributors and wholesalers. 

According to Question 2.4, QPs can run remote batch certification, provided they have access to all information necessary. This provision is valid for all EU countries, also those which normally do not allow this type of remote procedure. QPs can also run paper-based audits of site supplying the active substance should the on-site audits not possible due to travel restrictions. 

QPs are responsible for the verification batches of investigational medicinal products imported from third countries are compliant with the terms of the clinical trial authorisation and manufactured in accordance with quality standards at least equivalent to GMP requirements applied in the EEA.

Regulatory authorities should be contacted by MAHs experiencing difficulties with the approved quality controls, so to present an adapted control scheme based on a risk-based approach (Q 3.1).

The guideline also provides indication of the priorities and timing to communicate adverse events for drugs used to treat Covid-19, including those used off-label (Q 4.1). Question 5.1 discusses issues related to labelling and packaging of products to be exported in other EU countries, establishing the possibility to avoid translation into the relevant official language if there are severe problems of availability of that medicinal product in the Member State. 

A fast-track route for the approval of Covid’s medicines and vaccines

The wide diffusion of the Covid-19 infection at the global level asks for accelerated regulatory procedures in order to rapidly make available new therapeutic options to patients. “Together with our scientific committees and working parties, we have adapted our procedures in order to significantly shorten our own regulatory timelines for the review of new medicines and vaccines against Covid-19,” said EMA’s Executive Director Guido Rasi. “However, the rapid approval of therapeutics and vaccines will only be possible if applications are supported by robust and sound scientific evidence that allows EMA to conclude on a positive benefit-risk balance for these products.”

The Agency’s emerging health threats plan represents the basis of EMA’s planning to make available accelerated procedures, which are managed for review by the above mentioned Covid-ETF Task Force. Rapid scientific advice is the central measure for new products under development, waiving the respective fees and with a length for the procedure reduced to 20 days. Rapid agreement of paediatric investigation plans (PIPs) and rapid compliance check are other options available, all requiring submission of a “well-prepared dossier” to EMA. Procedures of authorisation and post-authorisation are expected to require less than the standard 210 days maximum. Rolling review, in particular, can be used in a public health emergency to assess data for a promising medicine as they become available, while accelerated assessment can reduce the review time to less than 150 days. 

New M&A dynamics in an uncertain Covid-19 environment

Giuliana Miglierini
-
0
New M&A dynamics in an uncertain Covid-19 environment

The total Mergers & Acquisitions (M&A) deal value in 2019 for the pharmaceutical and life sciences sector reached $358,5 billion (+62% vs 2018), according to a report from Price Waterhouse Coopers (PwC), with 12 mega-deals among the almost 250 totally closed. The largest deal in 2019 ($99,5 billion investment) involved BMS and Celgene, followed by the AbbVie/Allergan one ($86,0 bln).

Going more in detail in the different segments, pharma deals decreased 16% in volumes vs 2018 while remained largely stable in value, while the biotech sector experienced a great increase both in value and volumes. The increasing trend characterised also the Services sub-sector, while a slight decrease affected the medical device segment vs 2018. 

Expectations for 2020

The New Year which opened with the Covid-19 pandemic is accelerating the transition to new models of business also in life sciences, a trend which was already active in 2019 due to the strong turnover of CEOs and the combination of economic and regulatory pressures.

Year 2020 may see especially mid-size biotech’s acquisition ($5 bln – $10 bln, up to $20-30 bln deal value) – being at the moment the most dynamic segment as for the generation of innovation in the medical field – and many divestitures (either sale, spin-off or IPO) in the pharma segment, according to PwC. Both medical devices and services are expected to be quite active, with the former one characterised by the entrance of new industrial players looking for diversification of their traditional business. 

Large pharma companies should continue to invest in order to gain category leadership, says the report. Divestitures would make available funds to reinvest in innovation, namely in the oncology, cell and gene therapy segments. The Specialty Pharma and Generics sector is expected to be less active in 2020, even if some consolidation of mid-market players may occur. 

Private equity may play a primary role for example in divestitures, says PwC, thanks to the over $1.7 trillion dry-powder availability and the pro-active search for new opportunities. Early investment in companies capable to deliver innovative business models may also support a growth trend in the partnership segment, including alliances and joint-ventures.

Spin-off companies for no-core areas of business

The creation of spin-offs of entire areas of business made by large companies in the pharma and medical devices field is also an increasing trend often observed during recent years. This sort of operation may be linked to the move of part of the portfolios which are no more “core” to the company’s activities, says an article from Pharma Technology Focus, pointing the attention on spin-offs “generics divisions” created to host older and well established products which ceased patent protection. 

This approach may also lead to a steady flux of incomes for the parent company coming from legacy brands, suggests Pharma Technology Focus, as it may be expected that the pandemic will slow down many innovation projects. The presence of diversified products within the spin-off portfolio would diminish the risk of this type of operation. It is the case, for example, of the NewCo announced by Merck in early February 2020, which should host the women health portfolio, well-known legacy brands and biosimilar businesses.

The production of active ingredients is also a critical step which may be the target for a spin-off creation, suggests the article, as acknowledged by the Sanofi’s initiative to create by 2022 a new company in Europe to produce six of its APIs. The importance of such a move on the European territory of the supply of active ingredients (and intermediates) has proven dramatically during the Covid-19 emergency, when China and India blocked their exports with a big impact on shortage of medicines experienced in European countries. 

It may prove difficult to find its way

Small biotech companies are currently the main driver for R&D and innovation, thus representing a main target for M&A deals operated by larger companies looking to revamp their pipelines. Many of these operations had historically proved unsuccessful to bring the expected results in terms of clinical success. Small biotech business may thus become the center of different rounds of pipeline refocussing and investments. From this point of view, a paradigmatic example is that of Millendo Therapeutics, which has been reported by Ed Miseta on Life Science Leader. 

The company was initially founded in 2012 as Atterocor by Julia Owens and other two researchers, as a spin-out from the University of Michigan with the target of developing the small molecule nevanimibe (ATR-101) to treat a rare adrenal cortical carcinoma (ACC). This project stopped after three years, due to the failure of the dose escalation studies in human patients. 

The company (now Millendo) – with the support of its investment VC’s partners – completely revised its strategy to focus on the acquisition of the MLE4901 project from AstraZeneca, a product to treat polycystic ovary syndrome which had already shown proof of concept in Phase 2 testing. Nevanimibe was also re-targeted against congenital adrenal hyperplasia. But again, despite the first encouraging results, in mid 2017 the MLE4901 project had to be stopped due to potential liver toxicity and inability to generate an acceptable risk-to-benefit ratio. 

The new challenge to ensure the continuation of the company ended up with a merger with the French Alizé Pharma, a small company working on livoletide, a product to treat the rare Prader-Willi syndrome, a genetic disorder causing insatiable appetite and resulting in metabolic issues. 

“First and foremost, I recommend surrounding yourself with quality people,” said Julia Owens to Life Science Leader commenting her experience. The Millendo story also teaches not to focus just on finance as the only driver to guide decisions, even during the most troubled times for the survival of a business, and to be intellectually honest with regard to ongoing projects, which need to be assessed correctly under a sustainable development perspective. 

Strategies and deal potentials after the Covid-19 crisis

Global industrial indexes have fallen in the first quarter 2020 due to the stop to many productions resulting from the spreading of the coronavirus infection. Another study from PwC explore the opportunities in the M&A area which remain open even in these times of great economic uncertainty.

“We’re clearly operating in a new M&A environment — one that will continue to evolve. Early trends, particularly around shorter-term deal tactics, are beginning to emerge, and soon there will be longer-term, more fundamental shifts in deal strategy, valuation and liquidity”, writes Colin Wittmer, US Deal Leader, from PwC’s blog.

It might prove a good period to close deals, suggests the report, as companies investing during a recession could outperform with respect to their competitors. “While deal volume has declined recently, fears of a full collapse similar to previous cycles may be premature. In short, a combination of factors has been driving a decoupling of deals from the broader economy. That decoupling is different from past cycles, providing a higher floor that should prevent deal activity from evaporating”, writes PwC.

The market of capital is quite healthy, and companies have many cash available in their balance sheets, as do also private equity firms ($2.5 trillion dry power); borrowing money is paying low interest rates. The economic crisis may cause the swelling of many businesses, suggests the report, resulting in many targets available for M&As, and a major role for players which already acted to safeguard and realign their business. 

PwC’s report also highlights the importance to be prepared to exploit this opportunity, focusing on best practices to be used to manage the deals and deepening knowledge of the lessons learned from previous recessions. The current cycle is different from the recent ones and needs a completely different approach to strategic thinking, say the analysts, including the emergence of completely new business models.

Not least, this shift may also impact on customer engagement: it is important to anticipate needs, suggests PwC, to prevent revenue decline. An aspect on which a big role is also played by the ability of the company to communicate a sense of steadiness to its clients both on the short- and long-term vision, avoiding any form of anxiety for the future. Talented workforce should be always retained, adds the report, working to the creation of an inspirational and unified culture able to support the future growth of the company.

Any reduction of activities must be strategically assessed and calibrated in order to ensure the maintenance of a good flow of revenues. Simplification of processes and procedures should be the focus of new investments, so to improve efficiency and free resources for the potential acquisition of new assets. 

Pharma workforce is moving forward post Covid-19

Giuliana Miglierini
-
0
Pharma workforce is moving forward post Covid-19

The industrial and human interactions landscape resulting from the Covid-19 epidemic may turn to be profoundly different with respect to just five months ago. As business processes are going to be completely redesigned to match the new request for social distancing and health security in the working environment, the workforce is called to be resilient and to redefine its approach to daily duties, as well. This may imply a redefinition of skills towards new, digital technologies and redeployment to new operative tasks. 

Analysts expect the transition would favour the recruitment of highly-skilled workforce, able to easily handle the new processes which will constitute the focus of rebuilding businesses on the long-term growth perspective. Several analysis have been published to draft emerging scenarios; we summarise the main points.

Trends in the pharmaceutical sector

The need to move some pharmaceutical active ingredients and intermediates production back to Western countries, as demonstrated by the supply issues emerged during the Covid-19 epidemic, may prove a leading driver to rise employment in the field on the long-term. The situation may be similar of the years ’20 of last century, after WWI and the Spanish Influenza pandemic, suggests an article by Lakshmipriya Nair on Express Pharma: this crisis ended up in a period of strong economic growth. 

Companies making vaccines and a new sales force design may represent two areas of future expansion for the pharma job market, according to Luna Corbetta from PwC: “Those that have invested in the employee experience, digitalisation and an agile operating model will be better positioned to emerge from this crisis”, she says. 

Employee engagement and capability should be the short-and mid-term focus, according to PwC Director, Anthony Waldron. While social distancing measures are key to the people back to productive plants, remote working asks for an optimisation to be reached through the use of accelerators and the empowerment of leaders and individual contributors.

R&D may become increasingly “virtual” in future, after many clinical trials were put on stop due to the Covid-19, and also the commercial sales forces are expected to move to a new digital mode of interaction with a broader set of possible customers. An example of the expected impact of Covid-19 on a pharmaceutical sales force has been drawn by McKinsey analysts (see here). 

The future may see a 30 percent-online/70 percent-offline working model to become permanent, is the suggestion. Telemedicine is another area expected to grow, as remote consulting might be the new standard for the interaction between doctors and their patients.

The Nair’s article deeply discusses the position of India as a possible future leader in pharmaceutical production, thanks to its well established generics industry. Here too, the true challenge is represented by the ability of the workforce to be receptive to changes and reskilling. An efficient supply chain management will represent a critical point for the future of many business, together with team building and leadership skills to deal with any crisis, suggests the article. 

Pharma employees would need to be highly flexible to adapt to new skills and roles required to manage smarter, automated manufacturing processes; “multi-skilled” workers may become the new standard for the sector. This transition has to be necessarily supported by intensive training; an already active example in this direction reported by Nair is the India’s Manipal Prolearn Pharma School of Excellence in Quality. R&D and IP protection may be other activities to be highly sustained by future investments, and thus requiring specialised workforce. 

The difficult road to ensure work continuity

A major challenge in last few months has been represented by the need to ensure business continuity while preserving the health and the jobs of workers. The challenge was faced greatly facilitating remote smart working, and preservation of social distancing in the industrial environment; an occurrence that might have seen many people not ready to these new modalities to approach job (see the analyses on the Accenture website).

According to McKinsey, the true challenge is not in handling remote working, but in the ability of the companies’ top management to “reskill and upskill the workforce to deliver new business models in the post-pandemic era”. At least three quarters of CFOs plan to shift at least 5 percent of previously on-site employees to permanently remote positions post-Covid-19, says McKinsey.

Chief Human Resources Officers (CHROs) are called to put in place contingency plans to support these workforce shifts. According to Accenture, the traditional forecasting models are obsolete after the Covid-19, and a five step process has been suggested to achieve long-lasting workforce resilience. McKinsey too depicted a six steps process to manage the transition from the workforce perspective. 

Predict demand shifts is considered essential to optimise decision making and should be supported by the use of analytics to identify and redefine skills and expose local labor-market supply and demand, also in other industries, suggests Accenture. 

Profiles of needed skills should be created to look for unique combinations of the required skills, aptitudes and interests, also with respect to broader roles. This sort of information should be also shared in a transparent way with the internal workforce. 

In dependance with the specific needs, impacted people may be shifted within or outside the organisation making use of a resilient ecosystem to sustain continued employment opportunities. According to Accenture, this may be pursued by building strong relationships and partnerships with the external environment, including non-profit organisations and the public sector. Alternative employment models and job design options may also facilitate the finding of a new job, while safeguarding attitudes and interests of each person. Artificial intelligence can also support the definition of skill gaps within the organisation, to be object of training to change the trajectory of the careers. People should be allowed to opt in and choose their learning, is the suggestion, while favouring also adjacent skills development to broaden possibilities to cover new roles.

A shared workforce resilience is finally considered important by Accenture to foster a more collaborative and less competitive talent ecosystem. It may be pursued by allowing people to explore the new possibilities while encouraging personal growth and ongoing learning opportunities. 

The urgent need to find a new employment

The economic crisis resulting from the generalised lockdown ended up with many persons loosing their jobs, thus needing to reinvent their life in order to earn enough money to sustain their families. It might turn to be a quite difficult challenge, provided that traditional skills may not be sufficient and “appealing” to find new opportunities.

According to Accenture’s, shared workforce resilience may represent a sustainable landing point to be pursued through a coordinated action between all involved actors, including governments, companies, citizens and non-profits organisation. The think-tank has developed the People + Work Connect platform in collaboration with several CHROs, an analytics-driven initiative aimed to pool non-confidential and aggregated workforce information by categories such as location and experience. The final goal is to make easier for companies to look for the workforce they need to hire and, on the other side, to support them to sustain their no longer needed employees to find a new job, moving large pools of people from one employer to another. 

The EU’s new Industrial and Pharmaceutical Strategies

Giuliana Miglierini
-
0
The EU’s new Industrial and Pharmaceutical Strategies

The European Commission’s new Industrial Strategy has been published on March 10th, quite at the beginning of the coronavirus global health crisis. The ecological and digital transitions and the target of a circular economy have been the inspiring principles of the document.

On March 23rd EP member Miroslav Číž presented a question for written answer focusing on the timetable the EU Commission is planning to discuss the new Pharmaceutical Strategy, in view of the possible need to cope with new health crisis in future. The main industrial think tanks in the pharmaceutical field also expressed their positions, which we summarise below.

The main features of the Industrial Strategy

A strong competitive environment, both internal and at the international level, is considered essential to support the development of new ideas by European entrepreneurs. Another action set forth by the Commission is the full implementation of the single market, as it would represent a pillar as for the role the EU can play in setting global standards. The reliability of European supply chains and the availability of a robust digital infrastructure are also envisaged as important factors to contribute the success of the new strategy.

This agenda is supported by the adoption of several other documents and actions complementary to the Strategy and specific to different lines intervention. These include the Single Market Enforcement Action Plan and Single Market Barriers Report, the setting up of a Single Market Enforcement Task-Force, composed of Member States and the Commission, the adoption of a new SME Strategy for a sustainable and digital Europe, the evaluation and review – and adaptation where needed – of the EU competition rules, including the ongoing evaluation of merger control and fitness check of State aid guidelines. The Commission also announced a Intellectual Property Action Plan as the tool to better evaluate the need for a revision of the current IP legal framework. The European Data Strategy will represent the basis for a new EU data economy, together with the creation of European data spaces in specific sectors and value chains. Other initiatives shall include a Digital Services Act to update and strengthen the legal framework for a single market in digital services, and the improvement of the working conditions for platform workers.

Future support to the competitiveness of EU’s R&D shall pass through public-private partnerships and the full implementation of the European Innovation Council by 2021. Place-based innovation and experimentation should be also encouraged, together with the availability of Digital Innovation Hubs to act as one-stop- shops for companies to access technology-testing. A new ‘Pact for Skills’ and the creation of a European Education Area shall support the formation of the needed talents. The Commission confirmed the intention to release its new EU pharmaceutical strategy in 2020, including actions to secure supplies and ensure innovation for patients.

The Strategy highlights some other instruments the Commission plans to improve to reach these ambitious goals. Among these are a White paper on an instrument on foreign subsidies, the intention to work for the strengthening of the global rules on industrial subsidies in the World Trade Organization, the adoption of the International Procurement Instrument and an Action plan on the Customs Union to reinforce customs controls. Many actions have been also announced in the energy and environment field.

EFPIA supports a strong R&D framework

The European Federation of the Pharmaceutical Industry Associations (EFPIA), representing innovator pharma companies, described in a post how Europe is gradually losing its traditional leadership position as for pharmaceutical innovation. “If the content of the Pharmaceutical Strategy undermines the ambition of the Industrial Strategy then there is a very real, immediate and tangible risk that Europe becomes simply a market for medical innovation that is researched and developed in other world regions”, wrote EFPIA’s DG Nathalie Moll is another post published on March 1st.

Just 25% of newly approved treatments originated in the EU in the period 2014-2018, according to EFPIA, while Eastern countries such as China are gaining an increasing importance in the R&D field. R&D pharmaceutical investments were approx. € 36,500 million in 2018, when the sector employed 765,000 people around Europe, also said EFPIA. The overall contribution to the EU economy would be over € 100 billion, plus other € 106 billion coming from the supply chain and employee spending (Efpia on PwC data, 2019)

Delocalisation and loss of investments are other trends which would hamper the European competitiveness, in favour not only of China, but also of the US, those R&D investments grew up 8% between 1990 and 2017, vs 4.5% of Europe. “What is crystal clear is that unless the Commission acts now, the trend will continue and even accelerate in the context of fierce global competition for life science investment”, wrote Nathalie Moll.

EFPIA asks for an open and constructive dialogue with the Commission to contribute to the definition of the new Industrial Strategy and the roadmap for Pharmaceuticals. Four main issues have been identified, starting from an IP framework able to protect industrial investments in medical research. A stable and fast regulatory framework would be also appreciated, together with a robust research infrastructure to support the delivery of next generation vaccines and treatments. This innovation should also benefit from a more equitable access for European citizens and patients. 

Optimise synergies of the interconnected pharma value chain

The structure of the internationally interconnected pharmaceutical value chain has been discussed in a post by Koen Berden, Executive Director International Trade for EFPIA. 

R&D on one side and sales and marketing at the other are the activities representing the higher added value for a pharmaceutical company, while production is at the bottom of the so-called “smiling curve”. Dr Berden attention went to the high-risk activities typical of R&D pharma companies, resulting in the often discussed difficulty to feed pipelines with industrially sustainable new candidate medicines. “So, one successful medicine has to earn back not only the R&D costs of the development of the medicine itself, but also the costs made for all other failed R&D attempts (9.998 out of 10.000) and compensate capital providers for the risk they have taken with their investments”, wrote Koen Berden.

Not only an industrial strategy, but also a trade strategy would be needed to allow the EU to compete in pharma R&D at the international level in incoming years, according to EFPIA’s expert. “In designing the industrial strategy, it is imperative to acknowledge two issues. First, the ‘assignment problem’ that each policy instrument should be assigned to the target on which it has the greatest relative effect, considering sector specific characteristics. […] Second, the fact that no one stakeholder can create industrial competitiveness alone: only a competitiveness movement that involves all stakeholders can be successful”, he says, while better depicting the specific goals of the four areas of intervention mentioned above. 

The position of the generic and biosimilar industry

Medicines for Europe, the association representing the generic and biosimilar industry, welcomed the new Pharmaceutical strategy. From its perspective, the uptake of generic and biosimilar medicines for improved access, the set up of a pan-European cooperation to prevent shortages by addressing the root causes and the delivery of guidelines on procurement of medicines under the EU Procurement Directive, including how to acknowledge investments in manufacturing and reward security of supply, should represent priority lines of action to draft the new policies.

The seminar “A European Union that ensures Patient Access & Sustainability”, organised by the Hungarian Permanent Representation to the EU with the support of the Croatian Presidency of the European Council represented the opportunity to discuss how to achieve a equitable and sustainable access to medicines across the EU. This also include access to medicines to treat cancer, as this disease is the main focus of the EU Commission’s Beating Cancer Plan. A stable supply of essential medicinal products, avoiding the risk of shortage, is another priority to be pursued tackling the economic and regulatory root causes and establishing a pan-European mechanism to coordinate EU and national policies to reduce the risk of shortages and to avoid spillover effects. A “focused, action-oriented high-level pharmaceutical forum, so that all together, policy-makers, regulators, payers, industry and other stakeholders concerned can achieve the right balance between health objectives and industry competitiveness in Europe. Europe can only succeed by breaking down silos to jointly define and implement policy reforms in support of patient access to medicines”, was the request of Medicines for Europe president, Christoph Stoller. 

The association is also member of the Industry4Europe Coalition, which groups 154 industrial associations. The initiative supported the definition of the new Industrial and Pharmaceutical Strategies with a position paper published in November 2019 and indicating seven priorities: business-friendly policy environment, sustainability at business core, upgraded skills and training, enhanced research and innovation, investment and improved access to finance, reinforcement of the European Single Market and strengthened trade and international market access. “We have always said that the European Union needs an ambitious industrial strategy to compete with other global regions that have already put industry at the very top of their political agenda. This new EU Industrial Strategy is an important step in that direction”, said Philippe Citroën, Coordinator of the Industry4Europe coalition welcoming the new Strategy. “It is now essential to turn this strategy into concrete actions and to maintain industry at the top of the EU political agenda in the coming years”.

New guidances for gene therapy

Giuliana Miglierini
-
0
New guidances for gene therapy

Gene therapies represent one of the most advanced frontiers in medical sciences. The development of advanced therapies requires a parallel effort from the regulatory agencies in order to promptly make available all guidance to support the development of new treatments. The European Medicines Agency (EMA) is investing a lot of energy in this direction; the last couple of years has been the publication of several new guidelines discussing different aspects of the development of advanced therapies including gene and cellular therapies. In addition the EMA has issued the final version of its new Regulatory Strategy to 2025, together with a summary and analysis of the comments received during public consultation. The following is a summary of the most relevant documents to complement the proposals from other stakeholders on how to implement this emerging technology.

GCPs for advanced therapies

The EU’s guideline for good clinical practices (GCP) specific to advanced therapy medicinal products (C(2019) 7140 final) was published by the EU Commission in October 2019. The guideline introduces supplementary provisions specific to ATMP products, as required by art. 4 of Regulation (EC) No 1394/2007 on ATMPs, amending Directive 2001/83/CE and Regulation (EC) No 726/2004.

In addition, gene therapies, as well as all other ATMPs, are subject to ICH E6 (R2) Good Clinical Practice Guideline (EMA/CHMP/ICH/135/1995, current version Rev. 2). Similarly,  Regulation (EU) No 536/2014 on clinical trials also continues to apply to all ATMPs, in particular with reference to the specific content of the cover letter, Protocol, Investigators Brochure (IB), and Investigators Medicinal Product Dossier (IMPD).

A unique product cycle

The main feature that distinguishes gene therapy products from other types of medicines is the complex cycle used for their production. This cycle involves many different actors, including hospitals, and is made up by the sum of critical operations and not only strictly referred to the gene editing technologies used to prepare the therapeutic construct. Logistics, for example, plays an essential role, as this sort of therapy is often characterised by a limited shelf life and needs dedicated tools and pathways for transportation from/to the production and administration centres. The administration step itself requires a specific formation of healthcare professionals who are in charge and the long-term effects of the therapy need to be carefully monitored in order to assess its safety and efficacy. 

Special clinical trial designs

As for all ATMPs, the clinical study of a candidate gene therapy requires the development of a special design for clinical trials, in order to capture all the specificities of this category of medicinal product. According to the GCP guideline for ATMPs, this includes the choice of the study population (which should allow the correct assessment of the risk/benefit ratio vs existing alternative therapeutic approaches), the risk of long-term and/or irreversible exposure to the therapeutic agent, special safeguards in cases of paediatric population or in utero treatments on foetuses, the advancement of the disease, possible sensitisation compromising transplant success and the impact of the pre-existing immunity.

Part IB of the clinical dossier has to provide information on the potential impact of previous or concomitant treatments and on possible consequences for the patient in case further treatments for the targeted disease are required. Also the risk of treatment failure should be addressed as appropriate, and informed consent must always to be collected from patients.

The administration of gene therapies requires pre-treatment of patients with a pre-conditioning regime, a passage that may become critical for the survival of some patients. Administration of the therapy should be undertaken only by authorised centres possessing dedicated emergency units as very severe adverse effects may occur. Other features to be considered include the definition of the cohort size number and active comparator (that may be unavailable), how to blind the study and the scientifically and ethically justified use of a placebo. 

A particularly challenging step in early-phase trials is the definition of the dose range, because bias might occur (e.g. the type of cells that cause the ADRs or the presence of inactive particles which may impact transduction efficiency and potency, etc.). Also the guideline indicates that a dose escalation strategy may not be necessary or appropriate; in any case, the Protocol must always provide the description and justification of the chosen dosage, as well as a clear and unambiguous definition of the “end of the trial”, as a long-term follow-up is often required. 

The guideline also provides an indication of how to run non-clinical studies, which should be based on the most appropriate and relevant in vivo and in vitro models. With this regard, a current major limitation is represented by the often unreliable information coming from animal models, due to incompatibility between humans and animal species. Traditional non-clinical pharmacokinetic or dose finding studies may be difficult to perform. The dossier has to provide a discussion of the rationale for the non-clinical development including those cases where the sponsor considers non-clinical studies are not feasible.

The quality and GMP aspects 

As for all pharmaceutical products, ATMPs and gene therapies have to comply with GMPs governing manufacturing and final quality; a version of the GMP guideline specific for ATMPs was issued in 2017 (C(2017) 7694). Among the many aspects that may impact on the quality of the final gene therapy are the variability of donor or patient-based starting material, how the disease status affects the quality of the starting material and the potential variability of the final drug product.

As already mentioned, the limited stability of this sort of drug requires great attention to the definition of the storage, transport and handling conditions, that often require very low temperature and rapid, fast-track delivery. All steps and temperature conditions along the supply chain have to be traced and documented, with adequate training to be provided by the sponsor. This is also true for the reconstitution step often needed to prepare the final formulation to be administered to the patient. Detailed information on procedures and a full traceability of the entire supply chain is a fundamental pre-requisite. 

It is also important to consider the role of medical devices associated to the medical product, for example in the form of a “combined ATMP”. In such a case, the dossier has to provide information on the characteristics, performance and intended use of the device and on its compliance with the relevant general safety and performance requirements established by Regulation (EU) No 2017/745 on medical devices.

Exemption from batch controls on imported ATMPs

In July 2019 EMA published a Q&A document (EMA/354272/2019) providing guidance on when exemptions from batch controls are acceptable for ATMPs imported into the European Union from a third country. QPs have the sole responsibility for the verification and certification that these ATMPs are manufactured in accordance with GMP, and possess a quality corresponding to the marketing authorisation dossier. All imported batches have to be re-tested, as given in Article 51(1)(b) of Directive 2001/83/EC;however,  if the product has been manufactured and tested in a country having a relevant mutual recognition agreement (or equivalent) with the EU, then Article 51(2) applies and the QP can relay on controls conducted in the third country. 

The Q&A document specifies the cases of exemption from re-testing in the EU: when just limited amount of material is available or the product is characterised by a very short shelf-life, provided the testing run in the third country was carried out by a GMP-certified facility. EMA specifies that this “exceptional exemption is primarily foreseen for imported patient-specific ATMPs (e.g. autologous product)”.

All requests for exemptions have to be supported by justification and provision of scientific data, to be assessed by the Committee for Advanced Therapies of the CHMP during the evaluation of the marketing authorisation procedure. A pre-approval inspection of the extra-EU GMP facilities can arranged, should a GMP-certificate not have been provided. With this regard, data transmitted to the European regulatory authority includes the total batch size and number of units required for batch release testing, the available stability data and proposed shelf life, the  analytical sampling plan and a GMP certificate issued by an EEA Competent Authority relevant to the particular category of testing at the facility located in the third country.

Use of out-of-specification ATMPs’ batches

According to Section 11.5 of the Guidelines on GMP for ATMPs, the use of out-of-specification (OOS) batches is allowed in exceptional circumstances when there is need to avoid an immediate significant hazard to the patient. A specific Q&As document on the use of OOSs batches was published by EMA in April 2019.

To activate this procedure, the sponsor has to provide the physician with all information about the evaluation of risks; the physician him/herself has then to request the batch, on the bases of the specific condition of the patient and the evaluation of the risks provided by the manufacturer.

The manufacturer is also responsible for investigating the root causes for the OOS; agreements specifying the respective roles must put in place when the manufacturer differs from the marketing authorisation holder (MAH) and/or importer. Any OOS has to be promptly communicated to the treating physicians within 48 hours. The EMA and the regulatory authority responsible for granting the MA to the site manufacturing or importing the medicinal product in the EU have also to be informed by submitting a Quality Defect report, when a patient has been administered or an OOS batch has been supplied for administration. As ATMPs are centrally authorised, national competent authorities of the treating site(s) may be involved checking that appropriate others have been informed. The patient has to be informed in lay language, and documents provided to him/her can neither transfer any responsibilities to the patient nor discharge the responsibilities of the MAH or the manufacturer. 

QPs cannot certify the OOS batches, but they are responsible for ensuring that all verifications of the batch have been performed. Details about the manufacture, testing, transport and storage of the product, the request of the treating physician and the analysis of the risks provided by the MAH/manufacturer have to be  recorded and documented. No obligations can be waived either h by the MAHs or by the QPs

Comparability considerations for ATMPs

Another Q&A document on comparability considerations for ATMPs was issued by EMA in December 2019 (EMA/CAT/499821/2019), addressing the criticality of the changes in the manufacturing procedure and the estimation of their impact on the characteristics of the final product. Comparability is aimed to demonstrate that no adverse impact on the quality, efficacy and/or safety profile of an advanced medicinal product has occurred when a manufacturing process change/transfer is introduced.

EMA’s advice in order to determine the amount of comparability data needed is to apply the Variation Regulation (for authorised ATMPs) or the clinical trial framework (for investigational ATMPs). The final goal is to built a suitable comparability program able to follow all steps in the development of a new gene therapy product with the required degree of flexibility. As might be expected, non-clinical phases of development will be necessarily characterised by high uncertainty and flexibility, but the acceptable level of flexibility is reduced when reaching the stage of pivotal clinical use, and subsequent marketing authorisation. 

The EMA also specifies that “vector based gene therapy medicinal products can be considered products more closely related to biotechnology in terms of manufacturing process and process controls. In this regard, ICH guideline Q5E can be more extensively considered and the comparability exercise can be focused on the capacity to address the changes with a careful analytical strategy”.

The so-called “comparability exercise” should be conducted stepwise, starting with analytical testing to confirm the physico-chemical and biological properties of the product. A critical analysis of the manufacturing process to identify all critical steps and in-process controls/materials is also needed. 

An evaluation of the proposed changes with respects of the resulting possible risks to the quality and the efficacy and safety profile of the product should be provided, using the risk-based approach and selecting relevant critical quality attributes to be compared. The generation of new validation data should also be considered as appropriate.

Comparison of processes is particularly important when a new manufacturing site is added. There is not a binding indication of the number of batches to be evaluated, it has to be established case by case. All steps along the process should be fully evaluated, justified and tracked, starting from early phase development and laboratory scale batches. A full comparability exercise is required for pivotal clinical studies; EMA discourage the introduction of substantial changes in the product during this stage of development, as they may affect the regulatory acceptability of the clinical data. 

A deep understanding and explanation of analytical methods should always be provided as the basis for the comparability exercise. Bridging of methods used during development needs also to be considered to support the comparability claim. Two approaches can be used to run this type of study: side-by-side testing of products in the same analytical run or comparison of post-change data to historical data obtained from pre-change process (not recommended, but acceptable if the former is not feasible). 

The impact of storage should also be considered, as it may reflect on materials; full real time stability studies are in general not required, while dedicated stability studies under accelerated or stress conditions may be useful. The use of healthy donor material is acceptable only with reference to patient’s material scarcity and/or ethical concerns, and it needs to be justified. 

An appropriate pre-specified plan with justification must be provided for the statistical approach chosen to evaluate data, including comparability acceptance criteria for the relevant quality attribute. Solely meeting specifications is not considered sufficient evidence to conclude on comparability.

Pre-commercial procurement of NGS in oncology

Next Generation Sequencing (NGS) is an essential activity to support the Beating Cancer Plan, which will represent the focus of the van der Leyen EU Commission in the healthcare space. The Commission announced the activation of the oncNGS project, started on 1 January 2020, under which eight health procurers from five different countries (Belgium, France, Germany, Spain, and Italy) will launch a pre-commercial procurement to develop an NGS tumour-marker analysis kit applicable to all tumour types.

The activities aim to provide an efficient molecular DNA/RNA profiling of tumour-derived material in liquid biopsies by means of pan-cancer tumour marker analysis kit including NGS analysis integrated with an ICT decision support system including analytical test interpretation and reporting. It would be thus possible to dispose of a common tumour profiling strategy allowing to provide equal access to innovative medicines. Other expected results of the project relate to the outcome research analysis after treatments with targeted therapies, and to the application of this type of testing to all patients. 

How to improve access

At the end of January 2020, the Alliance for Regenerative Medicine (ARM), the international organisation representing the advanced therapies sector, published a position paper on how to improve timely and effective access to cross-border healthcare in Europe. The document assumes that not all approved ATMPs are expected to be available in all EU’s countries, with additional barriers represented by differential Health Technology Assessment/pricing assessment and constraints to health budgets. 

ARM’s recommendations include the creation of a ‘one-stop shop’ ATMP coordination body at EU/EEA level, that may act as a broker between the different stakeholders and facilitate cross-border patient treatment and funding. Similar bodies should be created in each  country with regional funding or with multiple payers/insurers, to ensure authorities in the regions of treatment are compensated for the costs of treating patients from other regions. HTA activities should be also more aligned in order to produce shared product value assessment measures. Further measures may include new opportunities for cross-country collaboration, removing duplicative processes at national level, and adopting policy principles to enhance cross-country collaboration.

As gene therapy continues to advance, so must the regulatory framework be established to oversee it.

The impact of falsified medicines

Giuliana Miglierini
-
0
The impact of falsified medicines

The need to rapidly access medicinal products to cure or prevent a possible health threats is particularly challenging under emergency situations, such it might be the current coronavirus pandemic. Shortage of drugs might also occur in the pharmacies, prompting people to look for alternative sources of supply for the desired products. Dietary supplements (e.g. vitamins or herbal extracts) may also look appealing, especially to reinforce the immunity system. 

The internet offers a multiplicity of websites where to buy pharmaceutical products and supplements, often for significantly lower prices than those normally applied by pharmacies. There are many risks of fraud linked to this type of products, starting from the often unknown origin both of the website and of products sold thereof. While the European Medicines Agency (EMA) has warned about the risk falsified medicines to treat coronavirus are being sold on the internet, the OECD and the European Office for Intellectual Property (EUIPO) have published a joint report discussing the current status of pharmaceutical counterfeiting. 

“The study published today confirms the importance of building a strong system that is able to prevent falsified medicines from entering the legal supply chain through which medicines reach patients”, said Adrian van den Hoven, Director General of Medicines for Europe.

Falsified medicines at the time of the coronavirus

The European Medicines Agency (EMA) issued a note in March to alert the general public not to buy medicinal products to fight the coronavirus epidemic from untrustworthy websites. Falsified medicines might be dangerous for the health of people assuming them, as they may contain altered dosages of the active ingredient (both lower or higher), or even no API at all. Excipients too may be not pharmaceutical grade, thus posing further quality and safety issues. EMA says a great attention should be paid to websites claiming the availability of medicinal products to treat coronavirus which are not other way present on the market, as there is a very high risk they are counterfeited. 

European online pharmacies authorised to sell drugs and supplements on the internet can be verified by the presence of the special common logo on their homepage. Clicking on the logo redirects to the official lists of authorised online pharmacies which is managed by each European national competent authority. The lists for each country can be also accessed from EMA’s website.

In case of shortages, EMA’s advice for patients is to contact their doctor, pharmacist or national competent authority in order to receive guidance on possible alternative medicinal products that can be used instead of the missing one. 

China and India are the main hubs for falsified medicines

The Falsified Medicines Directive dates back to 2011 and is fully operative since 2019: all medicinal products commercialised on the European market have to carry the 2-D data matrix and anti-tampering device that enable pharmacists to verify their authenticity. Two IT hubs (EMVO & NMVOs) have also been established at the European and national level, respectively, to track all serial numbers in a collaboration effort between legislative and regulatory authorities and industrial stakeholders.

According to the OECD-EUIPO’s report, the global total value of falsified medicinal products was € 4.03 billion in 2016 ($ 4.4 billion). The report analyses data relative to years 2014-2016 and pertaining only international commerce, thus excluding falsified drugs manufactured and commercialised within a single country. Antibiotics and medicines to treat pain are the two more often counterfeited categories; other therapeutic areas which are often object of fraudulent activities include diabetes, HIV, cancer and the so-called “lifestyle” medicinal products, targeted to the maintenance of a correct lifestyle. 

The data exposed by the report have been gathered on the basis of seizures of falsified medicines made at customs. China and India, the main pharmaceutical hubs worldwide, are also the main sites of origin of falsified medicines, while transit often involves Hong Kong, Singapore, the Emirates, Yemen and Iran, says the report. 

The main points to be considered

Indirect costs have also to be kept in mind, for example resulting from the need to treat health conditions arising from the assumption of low quality falsified medicines by patients, as well as from the possible environment pollution resulting from their improper disposition. 

Counterfeiting is a serious threat for the competitiveness of the legitimate pharmaceutical industry. Loss of revenues at the global level due to this kind of practice is estimated by the report to be approx. €1,7 billion. From this perspective, the US appeared to be the country which suffers the most, with 38% of its pharmaceutical companies hit by infringement of their intellectual property rights; Swiss, Germany and France are also greatly affected by the phenomenon. 

Distributors are the most vulnerable point at the level of the pharmaceutical supply chain, while according to the report wholesalers suffer for lower criticalities. Another point of attention is linked to postal services, as often shipments of falsified medicines occurs as single, small parcels which are then capillary distributed by Posts or couriers. This represents a challenge as for the possibility to track and prevent the overall phenomenon, says OECD and EUIPO’s experts. 

Counterfeiting also requires the ability to closely replicate the packaging in order to render the falsified medicine indistinguishable from the original medicinal product. This sort of re-packing activities is often run, according to the report, in the many free exchange areas present at the international level, that thus represent another criticality needing attention. 

The Netherlands: Innovation in the academia and the industry

Giuliana Miglierini
-
0
The Netherlands: Innovation in the academia and the industry

Life sciences represent a healthy sector of the Dutch economy, with many universities and research centres as well as biotech and pharmaceutical companies working to the identification of new approaches to treatment.

NVFG, the Dutch association for pharmaceutical medicine, counts 848 members and five committees to support all the activities needed to develop, manufacture and distribute medicinal products. The Association Innovative Medicines groups 42 industrial members, mainly of which are involved in the development of biotechnological medicines. HollandBIO is the Dutch association for biotech companies, has 211 members, while at the country level there are almost 1800 companies in the life sciences sector, 682 of which are active in R&D.

We provide some examples of trends in Dutch R&D innovation referred both to the academia and the industry and that may impact on the activities of industrial pharmacists.

New models for R&D

The last decade has seen a progressive shift of the discovery step of drug development from the pharmaceutical industry towards universities and other R&D institutions. Collaborative research is becoming the “new normal”, a form of cooperation between public institutions and private companies which is also often rewarded by many financial incentives. Collaborative research allows the industry to decrease the risk implicit in R&D activities, especially with reference to early phase drug discovery, and novel and innovative approaches are now often identified within public research labs. 

Both the academia and the industry need to optimally exploit their respective special qualities in order to learn from one another so to reinvigorate the poor R&D industrial pipelines. There are many features characterising academic R&D activities that need to adapt to the completely different mode of working typical of the pharmaceutical industry. The reasoning on these features is essential in order to stimulate the debate on how to revamp the industrial pipelines.

The regulatory framework supporting drug development has also to modify in order to accommodate many new technologies, i.e. artificial intelligence and real-world-based evidence, which are promising to deeply innovate how a medicine is being developed and approved. The European Medicines Agency (EMA) has launched in 2019 its new Regulatory Strategy to 2025, that will inspire the activities programmed for the next five days.

The European regulatory system for medicines (the ‘EU network’, or EMRN) includes all national medicines regulators (human and veterinary) from EEA member states, EMA and the European Commission. A central role of the EMRN is to provide support to innovation and development of new and better medicines. This goal can be achieved through the regular monitoring of emerging scientific and technological innovations and a constant interaction with the different stakeholders, in order to assess the availability of skills and competences within the regulatory network, or the need for specific expertise. These are also crucial to the development of new regulatory guidelines on emerging and innovative technologies. 

The transformational research at the centre of EMA’s new Strategy includes among others cell-based therapies, genomics-based diagnostics, drug-device combinations, novel clinical trial design, predictive toxicology, real-world evidence, big data and artificial intelligence. Under this perspective, many are the possible competencies that can be provided by industrial pharmacists.

Many examples of innovation from the Dutch industry

The discovery and development of breakthrough therapies for diseases with large unmet medical need is the central focus of research activities of the Belgian’s biotech Galapagos. The company’s technological platform is based on the use of human primary cells to discover new molecular targets for small molecule drugs to act as inhibitors. The main focus area are rheumatoid arthritis, inflammatory bowel disease and fibrosis. The company’s pipe includes filgotinib, the first product already filed for registration, and a series if emerging drug development programs. In 2019, Galapagos signed with Gilead a transformative 10-year global research and development that should further contribute to the expansion of its R&D activities.

Pfizer Nederland’s platform of recombinant Adeno Associated Virus (rAAV) vector is used to create therapeutic genes able to directly enter target cells and act on the underlying cause of genetic disease. The company estimates tell of around 40 gene therapies that could be available for patients by 2023. Gene therapy hold the promise of a transformative cure, as it can restore the normal functions of the pathological gene, with a strong impact both on patients’ duration and quality of life. The main challenge to transfer this approach to therapy is reflected by size, both in terms of transferred genes and of manufacturing capabilities. Gene therapy based on rAAVs differs from the one using CRISPR-Cas9 techniques to integrate the functioning gene into patient’s chromosome. With rAAVs, the therapeutic gene acts as a blueprint to produce the missing or non-functioning protein. Diseases caused by single-gene alterations, e.g. hemophilia A/B and Duchenne’s, are Pfizer’s main targets for gene therapy based on this approach; the pipeline also include potential gene therapy solutions for a.o. Wilson’s disease, Friedreich’s ataxia and ALS. Marc Kaptein, Pfizer Nederland’s Country Medical Director, is also president of the NVFG, the Dutch association for pharmaceutical medicine, and board member of HollandBIO, the Dutch association for biotech companies.

Dutch Pharming Group is a biotech company specialised in the production of recombinant human proteins in host animals. Its main product, a protein replacement therapy for the acute treatment of Hereditary Angioedema (HAE) based on a recombinant human C1 esterase inhibitor, has been developed using the proprietary recombinant technology platform based on the use of the milk of transgenic rabbits. Under the guide of CEO Sijmen de Vries, Pharming new projects include the extension of the technology platform to develop new forms of administration of its leading product for hereditary angioedema, i.e. a liquid formulation to be administered also through nano-injections, for both prophylaxis and acute treatment of HAE. The pipeline is completed by the clinical development of protein replacement products in Pompe and Fabry diseases, the expansion of recombinant human C1 esterase inhibitor (rhC1INH) clinical development in pre-eclampsia, contrast induced nephropathy (CIN) and other potential large indications. Furthermore, the company has also in-licensed from Novartis the late-stage PI3K inhibitor (leniolisib), to be launched for the ultra-rare disease activated PI3K delta syndrome.

The use of oligonucleotide-based therapeutics to treat inherited retinal diseases is the main focus of ProQR, working at the development of RNA-based gene therapies for ophthalmology applications. Severe rare diseases characterised by limited therapeutic options are again the target of R&D activities. The development pipeline includes eight products to treat several forms of inherited blindness such as Leber’s congenital amaurosis, Usher syndrome and autosomal dominant retinitis pigmentosa. Another candidate medicine is targeted to treat Huntington’s disease. ProQR also generated two spin-out companies: Amylon Therapeutics is focusing on the development of therapies for diseases of the central nervous system, including a rare genetic disease which leads to strokes at mid-adulthood, called HCHWA-D; Wings Therapeutics is studying therapies for dystrophic epidermolysis bullosa.

Nanomedicine is an emerging field of development in pharmaceutical sciences. Teva’s nanoparticle albumin-bound (nab) paclitaxel, launched in 2019 in Germany (see here the EPAR), is for example the company’s first product of this category. Paclitaxel is a quite old, but key antitumoral drug, originally registered in 1993 as a concentrate solution for infusion. Despite the usefulness of the drug in treating many forms of cancer (i.e.breast cancer), its safety profile has been hampered by adverse effects (e.g.hypersensitivity reactions). This results in the need of using Cremophor EL and dehydrated ethanol as solvents to overcome the molecule’s insolubility in water, and in a complex procedure for administartion, requiring premedication with glucocorticoids and antihistamines and the use of non-PVC infusion sets. The current nanoparticles of paclitaxel overcome these issues, as they can be administered in the form of aqueous nano-suspension; this new formulation also showed an improved pharmacokinetic profile over organic solvent-based paclitaxel. The product is manufactured at Teva Operations Haarlem; the different steps of the procedure start from the formation of a nano-emulsion obtained by mixing paclitaxel organic solution with an aqueous albumin solution and subsequent homogenisation. This is followed by rapid dilution with saline to obtain a nano-suspension, where paclitaxel is non-covalently bound to albumin; finally, the organic solvent is removed by evaporation and aqueous saline rinsing.

1...8910...21Page 9 of 21

Newsstand

  • Supplement to n.5 - October 2025 NCF International n.2 - 2025
  • NCF International n.1 - 2025
  • Supplemento to n.9 - October 2024 NCF International n.3 - 2024
Newsstand
© © 2026 Tecniche Nuove Spa - All rights reserved. Registered office: Via Eritrea 21 - 20157 Milan. Share capital: 5,000,000 Euro fully paid up. Tax code, VAT number and registration with the Milan Register of Companies: 00753480151