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Giuliana Miglierini

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EMA’s vision on evidence by design to evaluate the added therapeutic benefit

Giuliana Miglierini
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EMA’s vision on evidence by design to evaluate the added therapeutic benefit

The new models supporting the commercialisation of the innovative therapeutics – mainly in the field of biologics or advanced therapies (ATMPs) – have to face the fundamental issue of the very high prices often associated to this kind of potentially breakthrough products. The value associated to the new treatments compared to the existing – and maybe cheaper – ones in becoming a determinant parameter to assess the overall benefit-costs ratio of new medicinal products (we wrote about new business models in the April newsletter).

The shift towards this model needs to rethink the entire development process in order to produce at each step all the necessary evidence needed to support not only the claims for the new medicine, but also the explicative details supporting a positive benefit-costs ratio. Regulatory and health technology assessment (HTA) authorities are then called to evaluate this ratio together with all the scientific and manufacturing information, in order to reach approval of the new therapeutic intervention and to determine its price and reimbursement.
The point of view of the European Medicines Agency (EMA) on how to achieve this final outcome has been discussed in a paper published in Nature Reviews Drug Discovery and signed by EMA’s Executive director Guido Rasi, the Agency’s Senior medical officer, Hans-Georg Eichler, and the Chairman of the Committee for Human Medicinal Products (CHMP), Harald Enzmann.

Evidence-by-design to win the challenge

The availability of a demonstrated “added therapeutic value” compared to already existing treatments is the challenge pharmaceutical companies have to afford to submit robust, evidence-based approval dossiers to regulatory authorities. According to the article by Rasi et al., the regulator is an active part of the process, as it has to support the industry in the proper understanding of what does truly represent an “innovative” medicinal product.
A clear explanation made by the regulatory authority of the benefits of a new drug at the approval time should represent the basis to justify an higher pricing. The request to the industry to produce data generated by the “evidence-by-design” approach to development should guide all the steps and activities – starting from early discover – needed to properly inform the final decision of the regulators. A strict interaction between pharmaceutical companies and regulatory authorities is then needed, suggests the EMA’s article, in order to better understand and guide from early phases the design of the clinical studies intended to support approval.

Innovation vs therapeutic value

There is still a gap between the concepts of “innovation” and “added therapeutic value”, as the first term does not automatically imply that an innovative candidate medicinal product does really represent a true added benefit on the ground of the possibility to successfully cure the target disease. The three EMA’s representatives highlight the importance from the regulatory point of view of the concept of “added therapeutic value”, as a failure in the ability to demonstrate such a benefit is increasingly used by many regulators and HTA bodies to justify the refusal for higher pricing or reimbursement of innovative products that are judged to present just limited or no clinical benefits over the existing alternatives.
From this perspective, the main proposal arising from EMA’s article is to authorise for marketing just those medicinal products able to demonstrate a true added therapeutic value. The representatives of the European Medicines Agency also suggest that the efficacy and safety of candidate medicines may be compared to the best treatment available at the time the clinical study is run, using a randomised, active control approach.

The limits of EMA’s proposal

Should the added therapeutic value become the central requirement to reach regulatory approval, much less new medicinal products might reach the market, thus limiting the flexibility of the R&D activities run by pharmaceutical companies and the availability of new benefits both for patients and healthcare systems. The article discusses the case of the “me-too” medicinal products, many of which have been able to differentiate from one another just after commercialisation, on the base of different safety and/or efficacy profiles, or because of different drug-drug interactions or fewer side effects.
Another possible bias to be considered, argue the experts from EMA, relates to the possibility to observe different therapeutic responses at the level of single patients. This may reflect on the increasing personalisation in the choice of the most appropriate treatment to be used for a specific patient on the base of its genomic, metabolic or proteomic profile: the “-omic” approach to the characterisation of sub-groups of patients more prone to give a therapeutic response to a certain treatment.
EMA’s representatives also highlight in the article the importance to consider the point of view of the patient itself, as for example he/she may prefer to pursue therapies having the higher efficacy or, on the other hand, may wish to limit as much as possible the adverse effects associated to a certain treatment. It is thus important, from the regulatory point of view, also to ensure the availability of many different therapeutic choices and approaches to answer the different needs of health.

Increase competition to decrease prices

The development of a new medicinal product is a very long and costly pathway, and pharmaceutical companies often try to identify selected areas of expertise within which they are able to develop a sort of technological monopoly in the generation of new innovation. An increasing competition between different companies in the simultaneous creation of new medicines for the same therapeutic target is suggested by EMA’s experts as a possible tool to tear down this sort of monopoly and to limit prices for similar medicinal products.
Furthermore, a more diffuse use – where ethically possible – of placebo as the comparator for clinical studies may represent a standardised base line for the determination of the true clinical benefit of a new candidate, is another suggestion advanced by the article. This may also prove useful to better compare different new treatments arising at different times: a major limit of the current approach is, indeed, that the comparison against the best-available comparator may result obsolete as meanwhile new, more efficace treatments enter the market.

Indirect comparison and absolute benefit

The proposed concept of added therapeutic value may be also considered, according to the article, at the level of the indirect comparison of benefits through targeted studies, i.e. based on a “mixed treatment comparisons” (MTCs) design where two products are compared using the data available for each of them in comparison to a third product. The main limit of the indirect comparison is the availability of common endpoints for the studies to be considered, being this the fundamental requirement to allow for the true comparison of the reported data. According to EMA’s experts, this issue still requires discussions involving all stakeholders to reach a final consensus on the definition and use of common endpoints.
The often misleading concept of “absolute” therapeutic benefit has been also considered by Rasi et al. in the article, suggesting that it may be overcome by a more explicit regulatory evaluation and communication of all different aspects involving comparative efficacy aspects of the benefit-risk evaluation. This approach may be also used to evaluate clinical studies run against placebo, and it may prove useful to better communicate – as requested by the stakeholders – the positive, negative or neutral benefits at the level of sub-groups of patients.

How to address the choice of an API supplier

Giuliana Miglierini
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How to address the choice of an API supplier

In the integrated pharmaceutical supply chain, the choice of a reliable supplier for the provision of the active pharmaceutical ingredient (API) is a critical point to be addressed to ensure the safe and constant supply and the quality of the final medicinal product. As stated by the Food and Drug Administration (FDA), “It is the manufacturer’s responsibility to understand and assess their manufacturing process, assess any changes to that process, and based on that assessment and understanding, ensure test methods utilised can detect impurities expected to develop during the manufacturing process”.

The importance of this assessment since the very beginning of the development of the API’s manufacturing process has been clearly evidenced by the sartans issue exploded in June 2018: the API supplier Zheijiang Huahai (China) has been put under increased supervision after the issuance by the European Medicines Agency of a statement of non-compliance with good manufacturing practice (GMP), prohibiting the use of its valsartan in EU medicines, while imports of irbesartan from Indian company Aurobindo has been also stopped. In both cases, the decision of regulatory authorities followed the identification of probable carcinogens and genotoxic N-nitrosamine impurities (NMDA and/or NDEA) in the APIs (read here more from EMA).

The core requirements to be kept in mind while selecting a new API supplier have been discussed in an article by Cynthia A. Challener published in Pharmaceutical Technology, starting from the experience gained while dealing with the sartans case both at the regulatory and industrial level. Another article by Rita C. Peters afford the theme of the qualification of APIs’ suppliers from the perspective to prevent counterfeiting of the final medicinal products.

Two years transition to limit the overall risk

Before June 2018, N-nitrosamines were not considered among the impurities identified in sartan-containing medicines used to treat hypertension, and they were therefore not detected by routine tests. These chemicals form during the manufacturing process of sartans containing in their structure the tetrazole ring. At the end of January 2019 EMA asked pharmaceutical companies making sartan-based medicinal products to review their manufacturing processes in order to certainly avoid the undesired production on N-nitrosamine impurities (see here the details for the maximum daily intake and limit for NDMA and NDEA during the transition period). Following this two years period, companies will have to demonstrate that their sartan products have no quantifiable levels (< 0.03 parts per million) of these impurities before they can be commercialised in the EU. The FDA is also investigating the possible causes leading to the formation of the genotoxic impurities.

Lessons learnt and opportunities for the future

Compliance to the impurities levels established by the pharmaceutical regulations may be not enough to completely exclude the presence of very low levels of toxic substances, is the first lesson coming from the sartans issue. According to the Challener article, a possible cause for the formation of NDMA and NDEA might have been the occurrence of a side reaction involving a trace impurity in a solvent. Recycled solvents may also contribute to possible undesired side reactions. Inadvertently cross-contamination of the equipment and/or reagents may be another possible cause, adds EMA in its referral analysis of the case.
Any lesson learnt opens the space to new opportunities, starting from a more accurate process of risk assessment, to improve the compliance to GMPs and even exceed their requirements in order to reach the maximum possible guarantee for the quality of both the API and the final product.

Where to pay attention

The responsibility of the qualification of the API suppliers falls upon the marketing authorisation holders (MAH), that are thus called to exert a detailed due diligence on all aspects – including also the scientific ones – that might affect the quality of the substances used in production.
The full “fate and purge” study usually performed during process validation is one of the possible points where to pay attention to identify the potential impurities formed during the process, according to the Challener article. Attention to the change control process may also help in better identify, for example, the impact of the decision to change a solvent with respect to the potential impurities associated with it. These should be features captured during the risk assessment exercise, together with consideration on the possible application of the M7 ICH guideline on the assessment and control of DNA mutagenic impurities to limit potential carcinogenic risk.

A task that according to the experts interviewed by Cynthia Challener requires the adoption of more sophisticated analytical detection methods compared to the routine ones used to control APIs or the final products. In any case, all changes to the manufacturing process of an active ingredient should be deeply and jointly analysed by the supplier and the MAH on the base of an impact assessment.

If competence is not high enough

A feature that may result difficult to be exactly assessed is, according to the Challener article, the real scientific competence of the API supplier. Advanced chemical knowledge is fundamental to foreseen and prevent issues that might occur during processing due to undesired reactions. This type of competence should characterise not only the industrial part of the game (both for the API supplier and the MAH) but also the regulatory authorities evaluating the dossiers.
The proper assessment of the quality and GMP systems of the supplier, and of the scientific and technical competence of its workers, is an important factor that should be always weighted prior to the choice together with the much more typical price considerations. This can be achieved by audits of its facilities, and it should be coupled, where needed, to considerations on the possible impacts that might derive from the process.
The level of competence can be also indirectly assessed by the analysis of the regulatory track record of the supplier, and of the corrective actions that have been put in place to answer observations. The investments made in up-to-date analytical equipment, adds Cynthia Challener, may also support the assessment of the expertise in the development of new chemical entities, the design of the experiments and process, the development of analytical methods and quality assurance activities.

Traceability of APIs

The problem of low quality APIs is even more pronounced when dealing with counterfeited pharmaceutical products, as the provisions established by the Falsified Medicines Directive do not impose any strict action to trace the supply chain of the active ingredients. But such a tacking process would be essential to guarantee the quality of the APIs, according the Peters article, not only to prevent counterfeiting, but also to improve the overall supply chain of regularly approved medicinal products.
As a matter of fact, it is often difficult to exactly trace all passages and companies involved in the supply of raw materials used to manufacture the active ingredients and/or final medicinal products. Routine identity testing – and even better testing of critical quality attributes – and a periodical re-validation of the supplier are among the actions suggested by the article, especially in the case a single supplier for the API should be available. Periodical validation of test results reported in the Certificates of Analysis provided by suppliers should be also run by the MAH in order to minimise the risk of using adulterated or low quality raw materials. There have been 20 companies cited by the FDA in 2018 for failure to adequately test incoming raw materials, reports Rita Peters.

Greece: The National Chamber of Pharmacists

Giuliana Miglierini
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Greece: The National Chamber of Pharmacists

The profession of pharmacist may be exerted according to several different pathways, each of which with its own peculiarities to be safeguarded by a relevant professional association. In Greece three distinct professional bodies are currently active, representing respectively graduate pharmacists who own and operate their own community pharmacy (the Panhellenic Pharmaceutical Association), all graduate pharmacists who do not own their own pharmaceutical enterprise in general (the Panhellenic Association of Pharmacists) and hospital pharmacists of Greek public hospitals (the Pharmaceutical Association of Hospital Pharmacists).

To overcome this fragmentation, a major goal set forth by the board of Panhellenic Association of Pharmacists is the creation of a National Chamber of Pharmacists, similar to those already present in many European countries. The new Chamber may better provide protection of the integrity and independence of the profession, as it would include all its different declensions.
The maintenance of a register of pharmacists may also be centrally organised, supporting the better monitoring of competencies. The National Chamber may be also involved in giving opinions on draft regulations and laws concerning pharmaceutical affairs, or on pre-and post-graduate education pathways of pharmacists, and it may have disciplinary jurisdiction over the professional liability of pharmacists.
We provide analysis of the French, Italian and Polish models of National Chambers of Pharmacists to help understanding of the potential offered by the creation of such a professional body in Greece too.

The French Ordre des Pharmaciens

The French National Chamber of Pharmacists (Ordre des Pharmaciens) is the central reference body for all pharmacists who are active both in Metropolitan France or in the overseas departments and collectivities. It is structured according to seven different sections, each representing a specific pharmaceutical professional occupation (apart from section E):

  • Section A – Community pharmacy owners;
  • Section B – Pharmacists working in the pharma industry;
  • Section C – Pharmacists working for wholesalers;
  • Section D – Employed community pharmacists;
  • Section E – Overseas;
  • Section G – Clinical laboratories;
  • Section H – Hospital pharmacists.

The administrative and jurisdictional roles are played by the regional Councils for section A and the Central Councils of the other sections. A central governing board is made by representatives of the different section Councils, and those members are elected for a six years mandate. Up to half of Council’s members can be renewed in half of their mandate, during elections held every three years.
The French Public Health Law (Code de la Santé, art. L.4231-1) establishes that the National Chamber of Pharmacists is responsible for safeguarding the legality and integrity of the profession, in fulfilment of a public service mission. This include the respect of professional duties, the protection of the integrity and independence of the profession, the monitoring of the competency of pharmacists and the promotion of public health and the quality of treatments, with a particular attention to the safety of professional actions. The Chamber organises and keeps updated the Pharmaceutical record (Dossier pharmaceutique), listing all the medicinal products provided to each patient over the last four months (21 years for vaccines, 3 years for biological drugs), prescribed by a doctor or advised by a pharmacist.
The French National Chamber of Pharmacists also represents the sector with the public authorities and assistance bodies and it can initiate civil actions before all jurisdictions to safeguard against direct or indirect prejudice to the collective interests of the pharmaceutical profession.

All pharmacists need to be registered with the Chamber in order to exert their profession in France, with the exception of public health inspection pharmacists, regional agency health inspectors, inspectors of the French Health medicines and Products Safety Agency, pharmacist officials or related roles in the ministry for health and ministry for higher education, not involved in any pharmaceutical activity, and pharmacists involved in active service in the health services of the land sea and air forces.
The registration is a formal act aimed to validate law requirements to exert the profession (qualification, competence, respect of ethical standards, independence, the holding of a dispensary operating licence, etc.), and it is supported by the presentation to the Chamber of the documentation pre-determined by law. Establishments where pharmacists work need also to be authorised. Should the pharmacist exert different types of pharmaceutical activities, he/she would be registered in all the relevant sections of the Chamber. Private practice companies (SEL) have also to register, in addition to single pharmacists operating within them. Upon granting of the registration, a certificate is released to the applicant, or motivation of refusal is provided. A tacit refusal period of three months is set for applications in the area of Metropolitan France. Any decision can be appealed before the National Council of the Chamber.

The Italian Federation of the Chambers of Pharmacists

In Italy the profession of pharmacist can be exerted by law upon registration to the local Chamber of Pharmacists. These are organised at the level of each single Italian county (101 in total), and are centrally represented by the National Federation of the Chambers of Pharmacists (Federazione degli Ordini dei Farmacisti Italiani, FOFI). This last one – created in 1946 – is in-charge of the coordination of the local Chambers and represents at the national level all issues pertaining to the profession. It also organises the central registry of pharmacists. Elections to renew the board members occur every three years.

The institutional role of FOFI is similar to what is seen above for the French Chamber. The association exerts the disciplinary power with respect to the local Chambers and promulgate directives for the resolution of disputes regarding the profession that might occur between pharmacists and citizens or other bodies. The Chamber also supports the cultural growth and the professional development of its associates, and it designates its representatives within national commissions, institutions and other bodies. It collaborates with the government for the development of new laws impacting on the profession.

To be qualified for registration to the Italian Chamber of Pharmacists it is not enough to have completed the five year course of studies in Pharmacy or in Chemical and Pharmaceutical Technologies: a six months period of apprenticeship within a community or hospital pharmacy is also needed, followed by the passing of the National Exam. The Chemical and Pharmaceutical Technologies curriculum is more focused on the technological and industrial aspects of the preparation of medicinal products, dietary supplements and cosmetics, while the Pharmacy curriculum more generally covers all activities typical of the profession of pharmacists, including aspects related to health education and communication towards the public.

The Polish Pharmaceutical Chamber

The Polish Pharmaceutical Chamber (Naczelnej Izbie Aptekarska, NIA) represents all pharmacists working in the country, irrespective of their specific type of activity. It safeguards the autonomy and independence of the profession, working to code and promote ethics and deontology of pharmacists. The Chamber cooperates with the public bodies and other social entities, scientific societies, universities and research centres to solve issues regarding the profession or the public health. It also express the position of pharmacists on the organisation of the healthcare system and the pharmaceutical governance.
The Chamber’s representatives may take part to selective procedures regarding the profession. Its governing board may ask for new legislative initiatives, and expresses its opinion on pre- and post-degrees education pathways for pharmacists.
The Polish Pharmaceutical Chamber is responsible for keeping three different registries, the central register of Polish pharmacists, the one confirming the right for pharmacists from other EU countries to exert the profession in Poland and the disciplinary sanctions registry.
The Chamber is organised in thirteen different commissions, including those specialised on the different sectors of pharmacists activity (public or hospital pharmacies, wholesalers, etc.)

Switzerland: The new Swiss regulatory framework

Giuliana Miglierini
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Switzerland: The new Swiss regulatory framework

The Swiss law governing the marketing authorisation for medicinal products (Therapeutic Products Ordinance Package IV, TPO IV) has been completely renewed at the end of 2018 to harmonise definitions and procedures to the one used at the European level. The Package includes different ordinances both of the Federal Council and of the Swissmedic Agency Council, the majority of which have entered into force from 1st January 2019. Starting from this date, the new legislation is going to be used to process all applications received by the Swiss medicines agency.

Swiss GMP certificates are now available in Eudra-GMDP

One of the main features of the new Swiss regulatory framework is the harmonisation to EU-GMP and GDP rules. The relevant certificates for companies operating in Switzerland are now issued only in English. After the inspection of a Swiss-based production plant, the relative GMP certification is automatically inserted into the European Eudra-GMDP database, or it can be ordered (as well as GDP certificates) through the Swissmedic dedicated eGov Service portal upon registration.

A single order form can now be used for more than one operating site; it falls under the company’s responsibility to obtain any legalisations required. The public version of the Eudra-GMDP database (available since 2011) gives access to the information on medicinal products that is not commercially confidential or contains personal data. The harmonisation to the general rules used by EU countries should lead to an easier sharing of information and to efficiency gains for all stakeholders, said EMA in a note.

The entire procedure is now managed through the eGov portal, and certificates will be sent by Swissmedic just to the return Swiss address specified on the application form (and no more forwarded directly to the Federal Chancellery or to a consular service). With the entry into force of the new modalities, reference to GMP certificates needed fo regulatory purposes can be provided by citation of the relevant entry in Eudra-GMDP or by means of a downloadable file or printout from the data base. The new template for the request is similar to the one used by the European Medicines Agency (EMA). The “traditional” procedures still have to be used to request GMP compliance certificates that cannot be accessed via the Eudra-GMDP database.
The implementation of new rules is the consequence of the updating in August 2017 of the  mutual recognition agreement between the EU and Switzerland, active since June 2002. Swissmedic can now access the Eudra-GMDP database under a “read and write” permission, similarly to all other regulatory authorities having in place MRAs with the EU (i.e. the Japanese one is entering information into the database since 2013). The Swiss agency is also adding to the Eudra-GMDP database all the information on manufacturing authorisations related to Swiss manufacturers, comprehensive of the ones exporting to the EU.

Under the new Swiss legislation, in 2019 a new establishment licences shall also be put in place for production sites for active pharmaceutical ingredients (API). The licence will contain the list of all APIs produced by a certain site, corresponding to the list that will be automatically published on the GMP certificates. The Ordinance also introduce at art. 2 a new definition for batch release and GMP compliance, similar to the one typical of the EU regulatory framework.

The other new features

A better transparency of the entire regulatory approval process has been also pursued by publication of the “SwissPARs”, the assessment reports for human medicinal products with new active substances at the base of the authorisation decisions. The introduction of a pharmacovigilance plan, to be run according to Good Vigilance Practice, also harmonises Swiss to EU rules in the field of the safety monitoring of medicinal products. A particular attention is paid to paediatric products, for which the publication of a directory for off-label dosage recommendations has been established, together with new obligations and incentives for the pharmaceutical industry to promote the development of this kind of medicines. The definition of minimum requirements for the prescription of medicinal products has been also introduced.
The new Ordinance also introduces simplified authorisation options for certain types of medicinal products, i.e. those authorised in an EU or EFTA country, those based on traditional uses or used in complementary medicine and those already approved in a canton. The complete revision of the different supply categories of medicinal products is also expected to improve access to self-medication, as well as to ease the supply requirements. It will be easier for Swiss pharmacists to dispense self-medication medicines, provided the patient asked the consult of a specialist (but without need of a prescription). Pharmacists can also dispense some products under their own responsibility, i.e. anti-hystaminics to treat seasonal allergies.

The Swiss pharmaceutical market

Pharmaceutics is historically one of the main industrial sectors in Switzerland, contributing the 4,5% of national GDP in 2018 (data Interpharma). Almost half (49,2%) of the production for export (CHF 83.8 billion in 2017, 38% of total export) went in the EU, mainly to Germany (14,7%); import of pharmaceutical products from the EU reached 79,3% in the same year (CHF 35.3 billion , 19% of total import).

In 2017, the pharmaceuticals market grew 4.1% over the previous year to around CHF 5.8 billion, under the driving force of innovative anti-cancer therapies and new products to treat multiple sclerosis. The added value for the pharma sector was CHF 28,9 billion (€ 25,3 bln) in 2016. Pharmacies covers half of the market (50,4%), which also comprises self-dispensing doctors (24,8%), hospitals (23,7) and drugstores (1,1%).
Swissmedic approved 32 medicines with new active ingredients in 2017, seven under a fast-track procedure. The pharmaceutical industry almost doubled its workforce in the period 1995-2016, reaching 45,500 direct employees plus 181,000 indirect workers in 2016. Swiss-native pharmaceutical companies, such as Novartis or Roche, are among the main innovators in life sciences of the country. Investments in R&D made in 2017 in Switzerland by the 24 companies members of Interpharma reached CHF 6,8 billion (CHF 114 billion at the global level). Another CHF 500 million were invested in infrastructures (technical apparatus, machines and the equipment and production facilities).

Transparency, still a long road to reach the goal

Giuliana Miglierini
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Transparency, still a long road to reach the goal

Transparency in publishing results of clinical research is a very frequent requirement, especially with regard to public-private partnerships (we wrote on this in the March newsletter). Transparency should also be a permanent feature of a good supply chain management, tracking all movements related to a finish pharmaceutical product along the entire chain, from raw and starting materials.
If the final goal is clear, much less efficient are by now the actions undertaken to achieve it. We report a brief summary of latest data on different aspects of the transparency issue.

Still far to reach compliance in publishing data from clinical trials

Posting of clinical trial summary results in the European Clinical Trials Database Register (EUCTR) managed by the European Medicines Agency (EMA) become mandatory for sponsors since 21 July 2014 (see here EMA’s website), according to the requirements of the guideline issued by the EU Commission in 2012 (2012/C 302/03).

But compliance rates with these requirements are still highly unsatisfactory, says a retrospective cohort study published on the British Medical Journal in 2018 and showing that just half (49,5%) of the studies considered actually reported results. Many have also been the errors, omissions, and contradictory entries in EUCTR data found by researchers of the Evidence-Based Medicine DataLab at Oxford University led by Ben Goldacre.
The study considered 7,274 clinical trials (63%) over the 11,531 listed as completed (35,7% of the total content of the EUCTR database) and where results could be established as due under the 2012 guideline.

It is interesting to note that the higher proportion of unreported data (89%) refers to trials sponsored by non-commercial entities, while commercial sponsors showed a good tendency to post results (68,1%). Sponsors managing a larger number of clinical studies in the Register resulted also more prone to publish results. Almost one third (29.4%) of trials marked as completed gave no completion date, according to the Goldacre study. A limit of the research made at the Oxford University is the possibility that missing study results might have been published elsewhere that the EUCTR. Upon checking 100 unreported studies, for example, almost half (46) were found to have reported results in a journal publication and 5 in the grey literature. This supports, says the authors, the request to report results data within registries under a standardised format, to allow for a more reliable and efficient retrieval of relevant information.

The higher breaching tendency of non-commercial sponsors is attributed by the paper to a lesser knowledge of obligations set forth by the EU Commission’s guidelines. A particularly critical issue is represented by the responsibility falling to the principal investigator or administrative staff to insert study data and results in the EUCTR, a task that according to the Goldacre study might result complex to be achieved for the smaller cohort of trials. The Oxford team has also made available a web-based application, sponsors can use to identify their unreported studies. The suggestion for European institutions is to support the academy to invest in basic internal audits and administrative work, in order to be ready for the entry into force of the new Clinical Trials Regulation in 2022.
According to Ben Goldacre’s comments reported by Nature, another possible cause for not reporting can be find in the fact “some people may have an ideological commitment to a particular treatment, which may lead them to, either consciously or unconsciously, slow down the dissemination of findings contradicting that treatment”.

The situation is not better in the US

According to the Goldacre study, European rules on the publication of clinical research data are supporting an inclusive requirement for transparency, while in the US many exemptions to FDA Amendments Act (FDAAA) are in place that limit the impact of data published on the clinicaltrials.gov database.
A study run by the Universities Allied for Essential Medicines (UAEM) and TranspariMed focused on the attitude of 40 top US universities to comply with legal requirements on reporting clinical trial results since January 2017, and on activities made in the previous two years (2015-2017) to eliminate the backlogs of missing results.

The study found that just 15 universities are fully compliant to the US law governing transparency. The situation is very fragmented, with some of the major medical research universities that have posted results for less than half of their clinical trials (e.g. Mayo Clinic, UC San Francisco, Columbia University, UC San Diego, University of Cincinnati). Among best performers (100% reporting) are other leading medical research institutions, such as the Duke University and John Hopkins University.
The analysis considered 450 trials, for 31% of which results are still missing in the clinicaltrial.gov public registry; data were retrieved from the FDA Amendments Act (FDAAA) TrialsTracker website. The situation seems in any case to have improved, reports Nature, as according to an investigation run in 2015 by STAT 90% of all academic-sponsored trials in the period 2008-2015 did not published results within a year.

Partnerships agreements by the NHS are lacking transparency

This is the final conclusion of a recent investigation run by the BMJ in collaboration with academic researchers, that analysed the “joint working arrangements” (JWA) made between 194 NHS organisations and pharmaceutical companies in years 2016-2017.
JWA are used to manage collaborative research activities, and should respect the transparency criteria of the guideline published in 2008 by the NHS and Department of Health for England, and addressed also by a tool kit jointly published in 2010 by the NHS and ABPI (the British Association of the pharmaceutical industry).

All NHS organisations contacted by the BMJ under the “freedom of information” (FOI) request answered the request, but in about a fifth of cases (35, 18%) they refused to release the information. Where data have been made available, the BMJ team compared them with the ones obtained from the Disclosure UK database (collecting transparency declarations from pharmaceutical companies) and those published on websites of the NHS organisations.
According to the paper, 7% of trusts (13) said not to have kept central records of the partnership agreements, and 6% (12) argued the release of information would have caused prejudice to their commercial interests. Eight trusts (4%) claimed the time needed to find the requested data over-spanned the FOI request, and two referred to confidentiality reasons not to disclose information.
In 39 cases the NHS organisations declared not to have signed any JWA, while the investigation said to have found evidence of partnership agreements within Disclosure UK for a total amount of £ 2,6 million. Investments in joint working arrangements made by pharmaceutical companies reached £ 3 mln in 2016 and £ 4,7 mln in 2017. According to the BMJ, they would have been mainly targeted to accelerate the diffusion of new treatments; 93 projects would have specifically aimed to increase the use of products from the investing company.

Transparency along the supply chain

Cost pressures to obtain higher prices for finished medicinal products and very low costs for APIs and manufacturing processes, are the main driver sustaining the current profitability of the pharmaceutical industry. A driver that has to face the increasing pressure of governments, payers and health authorities to reach a more fair value for medicines on the market in order to allow the sustainability of the system and the access of patients to cures. Shortages of medicines caused by the diversion towards parallel trade is another mechanism often used to optimise profit for the industry. The way prices are negotiated at all levels are also often a grey area impacting on the overall transparency of the supply chain, with pricing representing a possible tool to manipulate the market (see here a commentary published on Pharma Logistics IQ).

Prices of the finished products are just the last element, but the lack of transparency originates far behind along the supply chain, at the level of the procurement of active pharmaceutical ingredients (API) and other raw materials needed to manufacture the medicine. 2018 has been characterised by the sartans issue, with recall of products from the market in EU and US due to the impurities of N-nitrosodimethylamine (NDMA) found in many different active ingredients manufactured in China (Zhejiang Huahai, ZH) and India (Aurobindo) (see here the latest update from EMA).

The integrity of the supply chain strictly depends from the transparency on manufacturing activities run in countries which are historically less used to comply with the very high GMP standards typical of Western productions. “The evidence is clear – a basic standard of safety must now be applied across the industry for APIs”, writes Andrew Rut on Pharmaphorum.
The inspections run by the European Medicines Agency (EMA) and the FDA on ZH’s Chuannan site in Linhai, China, revealed weaknesses in quality management and deficiencies in the way the company investigated impurities in its valsartan products. EMA has thus issued a statement of non-compliance with GMP, and excluded from the European market the API valsartan produced by the company. Zhejiang Huahai has been also put under increased supervision, a measure intended to provide the strict supervision of European regulatory authorities on all manufacturing activities of other active substances produced by the Chinese supplier. Inspection frequency has been increased, said EMA, and marketing authorisation holders for EU medicines has been required to perform additional tests on all active substances supplied by ZH. The EDQM also suspended in October 2018 the Certificate of suitability (CEP) of the Indian API manufacturer Aurobibdo Pharma, those active ingredient irbesartan was also found to contain low amounts of NDEA impurities.

But the true problem, according to Andrew Rut, would be the continuous research of the lowest costs possible for APIs, a trend that pushed an increasing delocalisation of productions towards Asia starting from the 1990s. The many passages needed to distribute APIs produced in China and India (almost 80% of the total) – up to the patient buying the finished product – may impact on the integrity and transparency of the supply chain. According to the article, costs considerations are still the factor that limits the possibility to secure back pharmaceutical manufacturing processes in Western countries. A new element that can support in few years the inversion of this trend is represented by the coming into force in 2022 of the new SPC manufacturing waiver, just approved by the European Parliament.

The use of the generic and biosimilar versions of many drugs is another tool widely used by payer to keep under control the high costs of medicinal products. The EU Falsified Medicine Directive introduced the request of serialisation starting from February 2019 to identify and track the supply chain for finished medicinal products, but it does not apply to APIs.
Inspection activities run by regulatory authorities on extra-EU manufacturing facilities can also greatly support an enhanced transparency of the supply chain. Andrew Rut reports a declining number of inspections run by the FDA in 2017-2018 (-10%) and 2016-2017 (-9%). EMA run in 2017 314 GMP inspections (on the 328 planned) and handled 161 notifications for suspected quality defects, plus 23 notifications of non-GMP compliance (see here the Annual report 2017). The European agency also run 12% additional routine GMP re-inspections of manufacturing sites addressed through exchange of information with international partners. EMA also actively supported the training of GCP and GMP inspectors and capacity building activities in China and India, and participated to workshops organised by the China Pharmaceutical Association of Plant Engineering in Taizhou and Jinan.

The EURIPID Collaboration for pricing and reimbursement

Giuliana Miglierini
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The EURIPID Collaboration for pricing and reimbursement

Pricing and reimbursement of medicinal products is a challenge to be faced by all the different national authorities to achieve the sustainability of healthcare systems while providing appropriate access to cures for patients. A better coordination in this field at the European level is pursued by the European Integrated Price Information Database Collaboration (EURIPID), a voluntary non-profit initiative grouping many authorities in charge of pricing and reimbursement in different member States. Its main objective is the control of pricing, in order to make medicines affordable and accessible. In Norway, for example, the local competent authority utilises EURIPID data to re-evaluate the prices of about 70% of products on the market on an annual basis to keep it updated again the fluctuations of the local currency against the Euro, explains the expert of the Norwegian Medicines Agency, Helga Festøy, from the blog of the European Commission.

Data sharing to access the database

The Collaboration was launched in 2010 and currently sees the participation of 24 European countries plus the European Commission (resulting from an initial invitation sent to 31 countries of the EU and EEA/EFTA and to 19 stakeholders. Croatia leaved the Collaboration in 2018). National competent authorities for pricing and reimbursement can access the EURIPID database that contains standardised data on official prices (and other information) of publicly reimbursed – mainly out-patient medicinal products – as published according to the Directive 89\105\EC. Access to the database is provided only to those countries available to share their data with the other participants, and this is subject to opposing voices that claim more transparency among the stakeholders (see for example here). Access is also provided on an ad hoc basis to researchers.

European countries part of the EURIPID Collaboration in 2015 (credits: EURIPID Collaboration)

The next step in the development of the project (to be run under the health programme) should see the inclusion in the database of information on the sales volumes of pharmaceuticals, wrote Festøy. The improvement of transparency shall be pursued also by the distribution among stakeholders of a Guidance Document on external price referencing (EPR), and the creation of a new dialogue platform.

A European project improve policies on pricing and reimbursement

The amelioration and implementation of the EURIPID database was the focus of a European project run in years 2015-2018 and aimed to achieve a better control on public budgets for medicinal products at the level of external reference pricing (ERP). The adhesion to the project (and to the EURIPID Collaboration) is voluntary, since the definition of the prices for medicinal products falls under the competence of the single nations.

The optimisation of the dataset and layout of the existing EURIPID database and website, the ability to provide the necessary information in a standardised web-based format and the development of the operational policy paper on a coordinated approach of national competent authorities regarding the use of ERP were the three key actions of the project. The project focused on the reviewing of the currently available datasets and on how to ameliorate and standardise them in order to provide a more uniform source of information to run the external reference pricing (ERP) procedures.
In the first phase of the project a User’s Requirement Specification document was drafted and shared with the participants, after formal approval by the Board of Participants of the Collaboration. This has been followed by the development of the EURIPID website and the update of the country “fact sheet” providing country-specific background information important for the right interpretation of the prices, which has been integrated into the website.
Data are provided by national competent authorities in a standardised format and are upload to the system using and improved procedure as for quality assurance measures and encryption of data. EURIPID provides also information on sales volumes and on the existence of managed entry agreements (just for 5 countries).

The technical Guidance document

The “Technical Guidance Document on External Reference Pricing” consists of an overview of the 12 principles governing the initiative and a detailed technical background report explaining how the principles were developed. The project also allowed to renew many functionalities of the database, both in the field of the general improvement of the informatics interface and the subsequent inclusion of new pieces of information.
The drafting of the Document was based on the reviewing of the literature and best practices on ERP in Europe. The document analyses how to mitigate the possible negative effects of ERP on patients’ access to medicines, while it does not discuss the appropriateness of ERP or the suitability of alternative policy options or approaches. The final technical document is mainly targeted to experts of the national competent authorities dealing with pricing and reimbursing of medicinal products, and it may prove useful also for other stakeholders involved in the process.

Transforming Big Pharma’s model

Giuliana Miglierini
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Transforming Big Pharma’s model

The third millennium is seeing a profound evolution of the pharmaceutical business model: no more large, diversified companies running R&D projects in multiple global hubs developing products mainly targeted to primary care. This model was typical of the 1990s and early 2000s; the deep impact of emerging new biotechnologies has then caused a shift towards a major focus on the development of specialty products and biologics. The expansion towards not yet mature emerging markets is another driver sustaining the pharma business. R&D activities are now mostly run within innovation clusters on the base of public-private partnerships greatly involving the academic researchers. The evolution of the model for pharma business during in years 1995-2015 has been analysed in detail in an article by Ajay Gautam and Xiaogang Pan published in Drug Discovery Today.

The declining of mergers & acquisitions

“Bigger is better”, i.e. the research of economies of scale was the driver of many M&A deals up to 2005s, says the study, but the final outcomes often showed poor results as they have been characterised by a lack in cultural integration of the merging companies. The following ten years saw a shift towards a more “leaner and focused” model, with companies more focused on their areas of strengths, thus disinvesting non-core assets. In this period M&A operations were targeted to build a strategic complementary expertise, and financial engineering based on tax inversions played also a role in many deals closed in the recent years, say the authors.
The last decade has been characterised by emerging markets – Asia (especially China), Latin America (Brazil), Russia, Middle-East and Africa – sustained by the growth of the local middle class and the consequent request for more healthcare. The dynamics of patent expiry in the different geographical areas are another factor to be considered to fully understand the increasing role played by many primary care products in these markets, explains the article.

The new paradigm of research and business

Big, hub-based R&D silos were the characteristic of the 1990s model, using high-throughput technologies to solve scientific challenges, while attention is now more paid to innovative, breakthrough technologies developed in strict collaboration with the university. These technologies can then be adopted by big pharma companies to produce new value-based products able to meet the needs coming from the market. “Medicine-as-a-service” is the new business model coming from this vision, those a primary consequence sees the moving of the headquarters of many pharmaceutical major companies in the closed proximity of leading innovation clusters.
Biologics and specialty products have become a major component in the pipeline of many companies (up to 58% for Lilly and 44% for BMS, according to the Gautam’s study), supported by the increasing relevance of personalised medicine, companion diagnostics and an ad hoc regulatory framework; on the other hand small-molecule-based products for primary care are experiencing a declining phase.

Paul Tunnah made an exercise to imagine how a pharma company 2.0 would look according to the new business model (read more here on Pharmaphorum).
It would include three core operating units, says Tunnah: therapeutic area interventions, product development and central operations. The first one should include all the different expertise needed to guide the patient’s journey in the disease. These includes, for example, the “customer story” to build the narrative of the journey from the perspectives of the single actors involved, and a “customer engagement” team working on-field to capture needs arising from doctors and all other components of the journey. Expertise in diagnostics, devices and digital health shall become an essential part of product development, extending far over the simple pharmaceutical development. The design of central operations of the pharma company 2.0 might also look quite different than today; the Chief Insights Officer may assume more importance as the responsible for the monitoring of all data and research, in close collaboration with the therapeutic area and product development, and for external data provider partnerships.

How artificial intelligence is changing medicine

“Big data” is the new mantra of the third millennium, and the acquisition of real-world data referred to the true contest of use for pharmaceutical products is becoming a key driver also to support regulatory decisions. Many are the examples of the application of machine- and deep-learning algorithms to improve the diagnostic and therapeutic processes available globally. Artificial intelligence (AI) should not overcome doctors, say the experts, but the future shall see an increasing complementarity of humans and AI to drive the journey into disease. The London Medical Imaging and AI Centre for Value Based Healthcare, for example, is a consortium between the academic, NHS and industry partners led by King’s College working to new models for value-based healthcare to optimise triage and target resources to deliver significant financial savings for the NHS and healthcare systems overall.

Artificial intelligence may also prove important to improve pharmacovigilance. This is one of the goal of the newly established International Working Group (IWG) on Signal Detection and Management in Pharmacovigilance, an initiative of the independent UK charity Drug Safety Research Unit (DSRU). The IWG groups experts from many big pharma companies, academia and regulatory authorities to help define the needs and propose ideas and guidance for the future on the basis of the most recent scientific evidences (see here the Pharmatimes report on the first meeting of the group).

The value-based model

Biopharmaceutical products are characterised by very high prices, with a deep impact on both the possibility to access the most innovative therapies and the ability for healthcare systems and other payers to sustain the costs of the new therapeutics. This has caused a deep, negative impact on the perception of the pharmaceutical industry, says Meagan Parrish on Pharmaceutical Manufacturing.

Giants as Merck, GSK and Pfizer are at the last positions of the 2018 RepTrack report for pharmaceutical companies, the analysis run by the Reputation Institute on the perception of companies in different industrial fields. At the bottom places are Sanofi, Genentech and Celgene. A falling reputation may be linked to the divergence between the expectations of its stakeholders and what the company is delivering, and for the pharmaceutical sector it might include six different factors, ranging from ethics to innovation, safety, sustainability, quality and security, reports Parrish in her article.

The “value-based” model is becoming the new paradigm, overcoming the prior “pay-for-services” model, explains Jim O’Donoghue from Pharmaphorum’s columns. A model that is sustained also by the associations representing the pharmaceutical industry (see for example Medicines for Europe).

Quality, and no more quantity, is the key characteristic of a value-based medicinal product: a quality to be measured on the positive outcomes obtained while treating patients in the real-world contest, away from the highly selected cohorts of clinical studies. These outcomes are also the main factor guiding new reimbursement policies in order to ensure the overall sustainability of the health systems. But a true “patient centric” approach – paying fewer attention to health professionals – is still needed to reach the goal, says O’Donoghue. Pharma companies are also starting to test new models in order to pro-actively engage patients along the journey, for example through patient support programmes (PSPs) or around-the-pill (ATP) services (to better involve the patient in the management of its disease). The Beyond-The-Pill (BTP) approach targets also the patients’ lifestyle that may play a role in keeping under control the progress of chronic conditions.

Smart medicinal products, which typically include a sensor within the pill to monitor the adherence to therapy, are another possible way to support the value-based model. Smart pills may help to reduce the inappropriate consumption of medicines and to cut costs to dispense therapies that patients then do not really use, says Angel Au-Yeung on Forbes.
These sensors can also track the physical activity of the patient and some physiological parameters i.e.temperature or heart beat, which are communicated to the healthcare team using smart devices for a better monitoring of the patient overall condition.

The first-in-class medicinal product of this type, Abilify MyCite to treat schizophrenia and other mental disorders, was approved in 2017 by the FDA; it has been developed by Proteus Digital Health and it is commercialised in collaboration with Otsuka Pharmaceutical. Similar approaches have been developed by etectRx, working to an empty gelatin capsule with an embedded wireless sensor, while Keratin Biosciences has reversed the situation and is developing a microchip hosting hundreds of sealed compartments, each of which can store up to 1 mg of a drug.

But such an approach to monitoring has to be carefully evaluated as its impact on the privacy of patients can be relevant, as smart pills exert an H24 control. Something that might frightened many persons, and that might be used, for example, by insurances to increase costs should the lifestyle result not to be appropriate (see here the comment on Consumer Reports).

EMA’s first guideline on medical devices integral to medicinal products

Giuliana Miglierini
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EMA’s first guideline on medical devices integral to medicinal products

Medical devices integral to a medicinal product are a category in continuous expansion, as a consequence of the need of many innovative therapies to be administered by mean of special, integrated devices, or to be monitored using dedicated in-vitro diagnostic tests (the so-called “companion diagnostics”, CDx).
The European Medicines Agency (EMA) has published the first guideline covering the theme of medical devices integral to medicinal products, under the form of Q&As. Companies are called to comply with the contents of the guideline for all marketing authorisation applications (MAAs) submitted starting from 26 May 2020.

A complex network of roles and responsibilities

This is just the first of a series of new guidelines EMA has planned in order to better support manufacturers in the identification of the different roles and responsibility of the complex network of central and national competent authorities – including the notified bodies responsible to assess the device and to issue the CE certificate – called to collaborate to reach the final approval of the integrated products. Under this category fall, for example, pre-filled syringes, pens to administrate insulin, transdermic patches or pre-filled inhalers. Products which are excluded from the application of the new guideline include, for example, the vials containing a medicinal solution packaged together a syringe for its administration.

The proper understanding of the flow of information across all different stakeholders, including the manufacturer of the device, will become essential from may 2020, when the new European Regulation on Medical Devices (EU 2017/745) will become fully in force. The new Regulation on In-vitro Diagnostics (EU 2017/746) will assume full validity from 2022.

“With the ever-increasing pace of innovation and the blurring of traditional boundaries between medicines and devices, it is inevitable for the Agency to assume new responsibilities in regulating complex medicines with a medical device component. The big challenge we face is to ensure we have the appropriate expertise and resources to adequately carry out these new tasks,” said Guido Rasi, executive director of the Agency.

Devices integral to medicinal products

Article 117 of the new MedDev regulation is the main focus of EMA’s guideline, thus the Q&As applies only to those devices that are commercialised as a unique, integral product with the associated medicine. Further requirements relate to the unique use of the device under the above mentioned combination and the impossibility of its re-use.

The MAAs’ dossiers submitted to EMA for this kind of products shall include also results of the compliance validation of the device. This can be fulfilled producing to EMA the declaration of conformity of the device or the certificate released by the notified body that runs the assessment. The device has to respect all relevant requirements listed in Annex 1 of Regulation EU 2017/745; if it is not possible to include in the MAA dossier the declaration or the CE certificate, and if the device is classified under risk class I-sterile, class I-measure, class IIa and IIb or class III, the manufacturer of the integral product has to provide EMA with the opinion from the notified body on the compliance to the general safety and performance requirements described in Annex 1.

Further implementation is expected

The first Q&A document released by EMA is a ‘living document’ that will grow in future as new details will be added, also regarding other categories of products. The Agency already announced that among the next to be considered are the devices incorporating a medicinal substance having an action ancillary to that of the device. For these products, the notified body in charge of their evaluation has to ask the scientific opinion of EMA – in the case the medicinal products is authorised under the centralised procedure, or contains human blood or plasma derivatives – or of the national competent authorities responsible for pharmaceutical products.
The same procedure shall apply to those medical devices containing substances or combinations of substances that are systemically absorbed by the body in order to exert their effect, and for in-vitro diagnostics (CDx) used to evaluate the eligibility of patients to a certain pharmacological treatment. Borderline products also fall under the application of the new guideline, as the European Commission can ask for EMA’s opinion in order to decide on the regulatory status of borderline products containing a medicinal component.

Belgium: Impact of the emergence of precisions medicines in clinical trials 

Giuliana Miglierini
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Belgium: Impact of the emergence of precisions medicines in clinical trials 

Belgium is among the leading European countries for number of clinical trials, with 507 new applications in 2016 and a total of almost 1,400 studies reached (22% phase 1, 28% phase 2, 39% phase 3 and 11% phase 4; data pharma.be). Investments in the sector of research into new medicinal products reached € 2.89 billion in 2016. The emergence of new, innovative types of therapies, i.e. advanced therapies (ATMPs) such as CAR-T or immuno-oncology products, asks for an updating of the traditional way to plan, design and run clinical trials.

The many challenges of personalised medicines

Precision medicine approaches are focused on the identification of small sub-groups of patients more likely prone to successfully react to certain therapeutic treatments. To identify such sub-groups – i.e. to select patients to be included in a new study – a wide variety of diagnostic methodologies are used to characterise specific biomarkers, many of which at the level of the patients’ DNA.
The choice of the most appropriate molecular testing, its validation, the coverage of its costs and the timing for use is one of the first barriers to be faced, according to the Educational book published by the American Society of Clinical Oncology (ASCO).

A barrier that also requires a strict collaboration between the biopharmaceutical industry and the manufacturers of these diagnostic devices in order to optimise the development of the respective products. Many innovative medicines are coupled to specific administration-approved companion diagnostics (CDx) falling under the medical device regulatory category. This development strategy is the one preferred in recent years by many regulatory authorities, i.e. US Food and Drug Administration, as it allows for a better identification of the eligible patients compared to other test methods. But ASCO warns about the possible greater discordance with the results from liquid biopsies, and underlines the need for clinical trials directly assessing solid vs. liquid biopsies and their utility in the decision-making and monitoring processes. Furthermore, explains the paper by Talia Golan et al. published in the Journal of Experimental & Clinical Cancer Research (JECCR), clinical biopsies are different from research biopsies, as the former aim to diagnosis and monitoring markers of response to targeted therapy, while the latter are part of a clinical trial protocol designed to answer specific scientific questions.

Genetic counseling services may be associated to the results of molecular panel testing, as a way to improve life style and prevent the emergence of pathologies that might be linked to the somatic or germline genetic profile of the patient.
The quality and quantity of the tumor tissue specimens collected, and their conservation in appropriate and standardised repositories (better if centralised), is another issue requiring attention. Time and modalities of conservation (i.e fixation with formalin) may also impact on the possibility to re-test archived samples, while techniques based on liquid biopsies are not yet validated in broader settings. More relaxed tissue requirements – e.g. with just optional tumor biopsies – are suggested by ASCO in order to improve patients’ participation to the studies.

How to optimise the study design

The first problem is to identify targetable molecular alterations valid from the clinical perspective, that may differ from the ones interesting under a non-research perspective. “Actionable” alterations are usually well defined, and their choice can be supported by computerised tools. An example made by ASCO is the LCI Integrated Knowledge database developed by the Levine Cancer Institute, which provides an automated synopsis of molecular alterations observed in patients and potential clinical trial matches on the base of the testing results specific for each patient. It is the provider itself (in the US) that can then choose the clinical trial more suited for the single patient, sending an email notification to the study coordinator.
The new interpretation of toxicity data from early phase studies on ATMPs has been discussed in the JECCR paper. The complexity of many forms of cancers, often associated with more than a single mutation, has caused a shift of paradigm that overcome the highly selective molecular testing to focus on unbiased whole-genome/whole-transcriptome testing. This is reflected by an increase of the number of “adaptive” or “umbrella” study designs, which according to the authors allow to rapidly test multiple hypotheses, drugs, and biomarkers. The majority of phase 1 trials with immuno-oncology antibodies have not reached the dose-limiting toxicity (DLT) dose, thus the recommended phase 2 dose is usually based on maximum administered dose or PK data, explained Golan et al. Furthermore, being this kind of products generally linked to significant early efficacy signals, phase 1 studies are often based on expanded cohorts. This is a design requiring a strong infrastructural capacity to capture early toxicity signals, as ATMPs may also lead to very severe adverse effects.
The choice of the cohort size should take into consideration the needed statistical power, the data already available on the product and clinical precedents, the eventual delay in effect, the choice of the primary endpoints (progression-free survival-PFS vs. overall survival-OS). From the ethical point of view, the setting up of the study design should also take into consideration the need to run research biopsies, suggests the JECCR paper.

The financial impact

The costs to access precision medicine therapies might be relevant, and unaffordable by many patients. From the industrial point of view, explains the JECCR paper, risk-based monitoring (RBM) models require quite big investments to validate the integrity of the clinical trial process according to the requirement of the FDA. The adaptive options indicated by the agency to simplify the process – e.g. centralised data collection and monitoring – are yet not so much frequently adopted both by experimental sites and sponsors. The Golan paper also provide a discussion of the budget definition for a study, which is based upon the general principle of fair value and varies with respect to the geographical location of the sites involved. External budget has also to cover all the costs included in the internal budget. All budgets are then negotiated with the industrial sponsor on the base of a justification approach.
The suggestion to community practices coming from ASCO is to use umbrella research protocols, in which data are shared allowing for a reduction of the costs for testing. But this approach needs to close partnership agreements with the company providing the service, something that can be difficult for smaller practices. These may also experiment issues in preparing business plans, or in the setting up of the infrastructure to support precision clinical trials. On the other hand, benefits include the possibility to administer highly innovative treatments to patients and an improved quality of care.
Emerging countries such as Brazil are increasingly proposing themselves as a location to run clinical trials on precision medicines, says the Golan paper, on the base of the high population, mainly “trial naïve”, and the support of an increasingly robust regulatory framework compliant to ICH GCP guidelines. The lack of cancer patients registries, the frequent uncertainty on the respect of regulatory timelines and logistical and cultural issues are factors limiting this opportunity.

A strong network of partnerships

The correct functioning of the supply chain for precision medicine (and its rapid evolution) requires a strong collaboration among all stakeholder, including the regulatory authorities, and dedicated shared resources, personnel and access to facilities, both at a national and international level.
The wide implementation of companion diagnostics and therapeutics tools is limited, according to the JECCR paper, by the availability of adequate and accessible laboratories and their close interaction with the clinicians, the access to drugs and the establishment of multicenter networks or collaborative groups.
A multi-disciplinary leadership team is suggested by ASCO in order to keep always update the precision medicine programme and its development. The availability of Molecular Tumor Boards (MTB) may also facilitate the correct interpretation of the testing results by less experienced community practices, and can provide support to identify the optimal time to start treatment, or options available to patients not wishing to participate to clinical trials.

The Belgian hub for clinical R&D

Quite one third (29.1%) of the R&D run in Belgian hospitals and research centres is targeted to the development of new anti-cancer medicines, followed by research on nervous system diseases (9%) and virus diseases (7,2%). This year will see the termination of the ‘Pact of the Future’ signed in 2015 between the local government and the pharmaceutical sector in order to attract more R&D investments in the country, included clinical trials. A Pact that has also led to the promulgation in 2017 of the new Belgian Law on Clinical trials, supporting ultra-fast approval procedures, particularly for phase 1 trials (just 15 days). All applications are scrutinised by a national College to provide harmonised assessment, under the central coordination by the competent authorities and designated ethics committees.
Patient recruitment efficiency, the quality of research centres and a dense medical infrastructure are the main features pharmaceutical companies are looking for while planning for a new clinical study, according to a survey run by pharma.be among 45 innovative pharma companies. With its over 70 top quality hospitals, Belgium was one of the first European countries to launch in 2018 pilot projects to prepare for the entry into force of the new EU regulation on Clinical trials (EU 536/2014), coupled with the creation in 2017 of the new National Innovation Office, the central access point for scientific and technical/regulatory questions.

Plan S: the EU’s open source publishing project

Giuliana Miglierini
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Plan S: the EU’s open source publishing project

Open access (OA) publishing is getting increasing attention as a way to rapidly and transparently disseminate results of scientific projects funded by public resources. The goal at the European level – starting from 1° January 2020 – is to use OA for all publications resulting from research activities run using grants provided by national and European research councils and funding bodies. This ambitious target is pursued by the Plan S initiative, launched in September 2018 by cOAlition S. This network – created by the Open Access Envoy of the European Commission – groups 11 different national research funding organisations under the coordination of Science Europe, and with the support of the European Commission and the European Research Council (ERC). “Only results that can be discussed, challenged, and, where  appropriate, tested and reproduced by others qualify as scientific”, states Plan S mission.

“‘Knowledge is power’ and I firmly believe that free access to all scientific publications from publicly funded research is a moral right of citizens. On 27 May 2016, all Member States committed to achieve this goal by 2020. It is one of the most important political commitments on science of recent times and puts Europe at the forefront of the global transition to open science”, said Research Commissioner Carlos Moedas commenting the launch of cOAlition S and Plan S.

No monetisation to access science

Paywalls are one the the main barriers – quite an “anomaly” that “is profoundly at odds with the ethos of science”, according to Plan S, as it could hamper the possibility of other scientists to access the information and run new research. Scientific publishers should be paid just for the value of the services they provide, is the position of Plan S, not to access science. The suggestion for publishers is to charge the editorial services needed publish a paper (i.e. reviewing, editing, dissemination and interlinking), according to the minimal standards laid down in the 2015 ‘Science Europe Principles on Open Access Publisher Services’.

The embargo period is another characteristic that should vanish under the new vision of open access publishing. The transition period towards the new model, it’s Plan S proposal, may tolerate publication on “hybrid” journals, covered by “transformative” type of agreements, where the introduction of publication fees should take the place of subscription fees. The malpractice of “predatory publishing”, where quite no editorial services are offered to authors, should be discouraged through the adoption of robust quality criteria for OA publishing, such as those provided by the Directory of Open Access Journals (DOAJ) and the Directory of Open Access Books (DOAB).

Plan S ten principles

The ERC Scientific Council shall collaborate with Science Europe and other stakeholdersto reach the concrete implementation of the principles stated in the declaration. “In this process, it is important to make sure the new setting works for all, accommodating the needs of researchers at different career stages and coming from different scholarly communities and parts of Europe”, said the president of the ERC, Jean-Pierre Bourguignon.

Plan S’s principles states that all publications must be published under an open license, preferably the Creative Commons Attribution Licence (CC-BY), or a licence fulfilling the requirements of the Berlin Declaration. Authors should retain the full copyright of their publication, while funders should jointly establish a robust set of requirements for the services provided by high quality open access journals and platforms. Incentives may also be provided where appropriate to create such journals and platforms, as well as the infrastructure needed for their management.
Publication fees should be covered by funders or universities, not by individual researchers, using a standardised and capped approach to fees across Europe. Transparency and other policies from universities, research organisations and libraries should align to the request of funders organisations. The principles also state the importance of appropriate repositories for the long-term conservation of research data (see also here the February newsletter).

The “hybrid” model of publishing is assumed by Plan S to be not compliant with these principles. Plan S goals apply to all kind of scholarly publication, but the initial deadline of 1° January 2020 refers only to papers published in scientific journals, while open access to monographs and books should follow at a later date.

Mixed opinions from stakeholders

The consultation launched by cOAlition S on Plan S principles and proposed actions collected more than 600 comments from more than 40 countries.
The Biomedical Alliance in Europe (BioMed Alliance), grouping 29 European research and medical societies, has issued a statement in which it shows “certain concerns” about the scope and implementation of Plan S.
“In particular, some of our members see the plan as underdeveloped, the timeline as too ambitious and the content as too restrictive and inflexible”, is written in the opinion. While considering beneficial the move towards open access publishing, BioMed Alliance also highlights the facts that many not-for-profit health organisations often depend on the publication of their societies journals as a source of income. The quality of scientific journals should also be maintained by specifying quality and peer review standards. The reversal of fees to cover publication costs may result unaffordable for many scientists, that might also suffer limitations in their academic freedom and publication options, says the Alliance.

For the European University Association (EUA) (read here its position), the transition to open access publishing requires the coherent and concerted efforts of all major stakeholders including researchers, funders, universities, research performing organisations and governments. EUA considers laudable the goal to stop the phenomenon of “double dipping” (paying first to publish and second to access the publication through subscriptions), but the system should evolve so that costs are affordable for universities, and limit inflation costs.

From the Q&A’s webpage of Elsevier – the bigger scientific publisher – Emma Ducker claims the company to be “well placed” as a leading OA publisher with over 40 funding body agreements enabling compliance with OA policies. But the company’s “ongoing priority is to ensure that authors can continue to choose the journals and models of publication best suited to their research needs”. The publisher also emphasises that Plan S is still a “local” initiative, while its services are directed towards the global community.

The American Association for the Advancement of Science (AAAS, publisher of Science journal) answered the consultation with a detailed argumentation against Plan S, said “to create major issues” for the scientific publishing community. Among the criticisms by AAAS is the cap on article processing charges, that may undercut innovation and quality, the possibility to decrease authors freedom while eliminating hybrid journals and the forcing towards publishing under a particular type of license (CC-BY).

Springer Nature’s data show OA articles attract greater citations, higher numbers of downloads, and increased wider impact, says the company’s Chief Publisher Officer, Steven Inchcoombe. “The last thing we wanted was to be viewed as somehow anti-OA”, he wrote commenting the closure of the consultation. The publisher of Nature journal sees some potential risks that might have counter-productive consequences. Growth of both supply and demand should be pursued to ensure sustainability of the initiative, while by now the attention is more on the supply side, he says.

A more exhaustive array of comments to Plan S can be found on the ScienceBusiness dedicated webpage.

Big pharma preference goes to the “green route”

While Plan S is working to examine all comments received during the consultation phase, the current situation of open access publishing specifically related to the pharmaceutical industry has been examined by a paper by Alfredo Yegros-Yegros and Thed van Leeuwen from Leiden University (NL), posted as preprint on SocArXiv.

Transparency in the publication of results of research run by (or with the participation of) the pharmaceutical industry is increasing, according to the paper, as acknowledged by the number of papers published in open access scientific journals having at least one author from a pharmaceutical company (among the 23 corporates considered in the study). This number doubled in the period 2009-2016, and exceeds the number of general, open access papers in the medicine-related fields.

The Dutch study considered 11 multinational companies with headquarters in the US, 9 in Europe, 2 in Japan and 1 in Israel. Data on their scientific publications have been collected with relation to all their subsidiaries and acquisitions, profiled using Moody’s Orbis database of corporate information. In years 2009-2016 the considered companies published 91,000 articles, reviews and letters, 32.2% of which are open access.
The so-called “green route” is the option generally preferred (80,3%) by large pharmaceutical companies, thus publishing their papers into an open access repository (PubMed Central, CrossRef or OpenAIRE), even if this option showed a declining trend over the period considered. Less used by industrial authors is the “gold route” (19,7%, but with an ascending trend in the period considered), where papers can be accessed freely directly from a publisher included in the DOAJ list (Directory of Open Access Journals) or the ROAD list (Directory of Open Access scholarly Resources). A reason for the preference for the green route might be, according to Kyle Siler from Utrecht University, commenting the study from Nature columns, the enhanced rapidity for publishing compared to high-profile journals.

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