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Αccelerated assessment of PRIority Medicines (the PRIME programme)

Giuliana Miglierini
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Αccelerated assessment of PRIority Medicines (the PRIME programme)

After two years from the launch of the EMA’s PRIority Medicines scheme (PRIME), the European Medicines Agency published a report discussing its current state of implementation and opportunities to further ameliorate procedures to support and optimise development and reach a fast approval of innovative medicines for unmet medical needs. EMA also published an updated version of the guidance document on PRIME, questions and answers and the template for applicants’ requests.

Early dialogue and regulatory support

The first three applications for marketing authorisation of new products developed under the PRIME scheme are currently under evaluation by EMA and are expected to gain opinion during 2018. Central to the PRIME scheme is the reinforcement of early dialogue and regulatory support to the industry. Since 2016, EMA has accepted just 36 (21%) of the total 177 applications received for eligibility to the PRIME scheme. The medium number of applications per month (8) has kept constant during the two years of activity of the scheme.
Oncology and haematology have been the therapeutic areas more represented, together with infectious diseases, neurology and psychiatric disorders. 83% of the approved applications concern rare diseases (for example, to treat achromatopsia associated with defects in CNGB3, X-linked hypohidrotic ectodermal dysplasia, primary hyperoxaluria type 1 and osteogenesis imperfecta types I, III and IV) and 44% were targeted to paediatric patients. Two of the six requests in the field of infectious diseases and vaccines have been approved for the treatment of septic shock and chronic hepatitis D, respectively.
The majority of the approved medicines (22) also received a scientific advice from EMA; notably, many of the 37 requests for advice also contained an input from health technology assessment bodies and patients. The majority of applications referred to chemical products (42%), followed by biological products (25%) and advanced therapies (AMTPs, 25%). This last category is often developed by small and medium sized companies.
According to EMA’s report, the quality of applications received by the Agency is generally good; more than 50% of applications to the PRIME scheme came from SMEs. Just eight applications have been considered out of scope, and thus not object of review. Noticeably, the proper time for application is considered to be the proof of principle (compelling non-clinical data and tolerability data from initial clinical trials) for SME and the proof of concept (preliminar clinical evidence) for non-SME applicants. Three of the eight applications received from SMEs have been granted eligibility. 72 over the 161 total requests coming from non-SME companies referred to phase 2 data (44%), 43 to phase 1-2 (26,7%) and 35 to phase 1 (21,75%). Very few have been so far the requests related to phase 3 data (3), compassionate use or case series (3) and literature (5). Only three are the applications advanced by the academia, a sign for EMA to continue to raise awareness on the possible support the Agency may offer to universities wishing to translate academic research into novel methodologies and medicines. Other requests rejected without review related to projects not clearly falling in the category of medicinal products.

The reasons to deny eligibility

Therapeutic advantage is the key to access the PRIME scheme: products are eligible if they can demonstrate the potential to significantly address an unmet medical need, for example by introducing new methods of therapy or improving existing ones. The request referred to a certain indication has to be supported by data demonstrating such a major therapeutic advantage to patient. The justification of eligibility criteria has to be provided by applicants at the time of the application.
According to the report, the first year of activity the scheme saw 14 requests denied because of a too advanced phase of development to ask advice. This decreased to three applications in the second year. The great majority (87%) of other requests were denied due to issues with robustness of the presented data to support the significant therapeutic advantage or inconclusive/insufficient effect with respect to magnitude, duration and relevance of endpoints. In a limited set of dossiers the proposed unmet clinical need was found to be unacceptable or not sufficiently justified. The new guidance issued by EMA better explains this point, highlighting how the PRIME committee might agree that an unmet medical need may still exist in the concerned condition (e.g. in a subgroup of patients or in view of limitations of existing therapies), but this need to be clearly supported by the applicant in its request.

The kick-off meetings

Multidisciplinary ‘kick-off’ meetings are a key component of the PRIME scheme, as the give the opportunity to identify issues, share the different positions and reach an agreement on the next steps in the development of the product. They occur after two-three months from entering the scheme and after the CHMP/CAT Rapporteur has been appointed; 31 meeting have been organised so far, with the participation of rapporteurs from EMA’s CHMP or CAT and the chairs and experts of relevant Agency’s committees. The preparation and conduct of kick-off meetings is also addressed within the new guidance on interaction in the context of PRIME published by EMA.

The meetings are intended also to discuss key development steps subject of future advice and the recommended regulatory strategy supporting development of the product. HTA bodies and patients organisations might also be involved on key issues, under the coordination of EMA acting as the single contact point to provide regulatory support under the PRIME scheme. The eligible products also receive confirmation of the potential for accelerated assessment at the time of the application for marketing authorisation.

EU’s proposal of an SPC manufacturing waiver

Giuliana Miglierini
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EU’s proposal of an SPC manufacturing waiver

The European Commission launched in 2015 its proposal for an SPC manufacturing waiver, within the more general context of the “Single Market Strategy”. This was followed between November 2017 and January 2018 by a public consultation of the Directorate for the Internal Market, Industry, Entrepreneurship and SMEs (DG Grow). The final proposal was published on 28 May 2018 in the Commission’s website (click here), and it shall now undergo examination and final approval by the European Parliament and the Council of Europe.
The waiver would allow the manufacturing of generic and biosimilar medicines intended for export even if the SPC certificate is still valid in the EU, provided that it had already expired or it is not into effect in the destination countries. The Single Market Strategy also includes the proposal of a single European SPC certificate and the update of rules governing patent exemption for research.

The proposal of the Commission

Some elucidations on the Commission’s proposal were published at the end of May 2018 in the form of Questions & Answers. Considering the very long time needed to develop a new medicine, thus shortening the length of its proprietary IP protection, Supplementary Protection Certificates (SPCs) have been introduced to extend this protection starting from the day the patent expires and up to five years. The average duration of SPCs granted in the EU is 3.5 years according to the Commission, being calculated to reflect the time needed to run clinical trials and testing. The annual number of SPC applications tripled from 1993 to 2013, and many of them are due to expire from 2020, leaving the space for many new generic and biosimilar medicines to enter the market.
European SPCs also protect the competitive potential of the Union in the domain of research, preventing relocation of cutting-edge pharmaceutical research activities in extra-EU countries. The proposal advanced by the Commission was based on the consideration that EU pharmaceutical companies manufacturing generics or biosimilar medicinal products are currently not even able to export their products in countries where the SPC protection has expired or does not exist, thus lowering their competitive position at the global level and enhancing the risks of delocalisation. SPCs also prevent EU manufactures to set up in the EU a production of new generics or biosimilars prior to the expiration of the corresponding patents, thus lowering also their internal competitive power.
According to the EU Commission, the SPC manufacturing waiver would generate an extra growth of at least € 1 billion per year in net additional export sales in the EU pharmaceutical sector, creating up to 25.000 extra high-skilled jobs over ten years. Small and medium sized companies are expected to benefit the most from the entrance into force of the new measure, as they experience more difficulties in delocalising production. The impact on the internal market would also be positive, as production would be already established for export and the products would thus be easily available within the EU starting immediately from day 1 after patent expiry. The savings in costs for public health is estimated up to 4% over the coming decade.
The Commission also intends to ensure clear safeguards to guarantee transparency of the procedure and avoid the possible illicit diversion onto the Union market of the generics and biosimilars produced for export. From this point of view, a notification to competent authorities would be needed to manufacture for export, and this information will be made public. The supply chain would be also informed that the product is intended for export only, and the product would be clearly labelled with an explicit logo (e.g. ‘EU Export‘) to reflect this, thus contributing to fight counterfeiting.

The debate at the EU Parliament

The proposal of the SPC manufacturing waiver has been subject of a written question to the Commission made by Parliament’s member Tadeusz Zwiefka (PPE) on 11 January 2018, asking confirmation about working going on the legislative proposal and, if so, when is this proposal would be scheduled to be submitted to the Council and to Parliament
“The SPC MW does not in any way violate the protection guaranteed by patents in the EU”, wrote Mr Zwiefka in its question.
The answer on behalf of the Commission was provided on 16 March 2018 by Ms Bieńkowska, recalling the different steps already taken by the Commission since the publication of the Single Market Strategy. The Commission’s representative mentioned 231 contributions received within the public consultation, and still under evaluation. “In parallel, the Commission has contracted several studies on these SPC related matters, with the final results of the remaining studies expected shortly. Regarding an eventual legislative initiative for an SPC manufacturing waiver, the Commission will carefully consider all options and their impacts on stakeholders, before taking any decision about a possible proposal”, stated Ms Bieńkowska in her answer.

The reactions of the industry

A deep concern about the SPC manufacturing waiver has been expressed by the European Federation of Pharmaceutical Industries Associations (EFPIA), representing originator industries. According to a statement published on its website, the proposal of the EU Commission would reduce IP rights and jeopardises patient access to innovative treatments. “It also sends a global signal that Europe is weakening its commitment to IP, putting this investment, these jobs, this opportunity for economic growth and the advancement of patient care in Europe at serious risk”, writes EFPIA.
According to Koen Berden, EFPIA’s leading trade expert, the research-based biopharmaceutical industry is one of the keys to be considered while discussing Europe’s strategy to remain a knowledge-economy. Its current investments in R&D in Europe are estimated to be approx. € 35 billion. “Unfortunately, the Commission’s proposal is inconsistent with its own ‘innovation-driven economy’ vision, jeopardising long-run innovation potential and dynamic benefits for uncertain short-term (and low-value) gains. The proposal to introduce an SPC manufacturing waiver is all the more striking given the extent to which other geographies, notably China, are moving in the opposite direction by strengthening their IP frameworks; aiming to become the Europe of tomorrow.”, said Koen Berden in the statement.
Of the complete opposite position is the European association representing manufacturers of generic and biosimilar medicinal products, Medicines for Europe, which published on its website several documents in support of the Commission’s proposal. With the SPC manufacturing waiver, is its position, EU and non-EU manufacturers would compete on the same level, while in case of delocalisation of production the loss of direct jobs is estimated in 25.000 units (plus 100.000 indirect). The possibility to export under the waiver might also generate € 9.5 billion net sales for the EU pharmaceutical industry and € 3.1 billion savings to EU pharmaceutical spending.
Upon publication of the final proposal, Medicines for Europe called on the European Parliament and European Council to rapidly adopt the SPC manufacturing waiver, but also expressed some concerns “that the legislative proposal does not fully address the unintended effects of the SPC Regulation, specifically production for ‘day 1 launch’ in Europe after SPC expiry”. According to the Association, “the draft also contains a few anomalies that undermine its stated intentions and give limited practical effect to the amendment for SMEs which hope to benefit from this opportunity”.

How artificial intelligence is changing the pharmaceutical industry

Giuliana Miglierini
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How artificial intelligence is changing the pharmaceutical industry

After an initial phase when the potential impact of artificial intelligence (AI) on the pharmaceutical industry has been mainly discussed in relation to marketing activities and the gathering of insights from clients, the time is now mature to better explore the many other possible applications of AI in the field of drug development and commercialisation.

The exponential growth of the market

The annual growth rate of the market of artificial intelligence for healthcare applications has been recently estimated by Global Market Insights to be 40% CAGR (Compounded Average Growth Rate) per year up to 2024, starting from a value on $ 750 million in 2016.
According to the report, China should be the faster growing country (45% CAGR), followed by the United States (35%), while Great Britain is the leading country in Europe. Barriers to entry this new industrial sector are represented by the very high initial costs and the possible negative impacts on human jobs, that will be increasingly replaced by automation.
Future might become difficult for companies still pursuing a more traditional business model, according to a study from EY: should they not adopt a more innovative and AI-based model, more than 75% of organisations in the life science sector currently listed in the Fortune 500 are expected to exit such list by 2023.

Non traditional players are increasingly active in the filed and gain increasing importance in the competitive scenario pharmaceutical companies have to face. IBM Watson, Google’s healthcare branches Verily and Deep Mind Health or Amazon itself, which recently entered the sector as healthcare provider in collaboration with JP Morgan and Berkshire Hathaway, are just few of the many possible examples of such non traditional players (you may find some more exhaustive ones in the article from techemergence)

A new industrial revolution in drug discovery

But the great potential of artificial intelligence shall become fully clear when considering its possible applications to drug discovery. It seems an era ago since the Human Genome Project was completed in 2003; since then, sequencing capabilities and softwares for data analysis rapidly established themselves as the new paradigm for drug discovery thanks to the increasing availability of IT technologies and the institutional and governmental support to big data analytics’ policies. These enhanced analytical capabilities are crucial to fully elaborate the enormous quantity of pre-clinical and clinical data already available both within the pharmaceutical industry and public research centres in order to extract new possible targets for drug development, or to test already available medicines for activity in new indications.
A recent example is represented by the publication of the final results of the Pan-Cancer Atlas project, a collaborative effort run by “The Cancer Genome Atlas” consortium which took ten years to fully characterise more than 11.000 specimens of tumors from the genomic point of view. The result are 33 new families of tumors, reclassified according to cells of origin and molecular similarity, the type of oncogenic process and its progression and the analysis of the tumor signaling pathways.
In the UK, a consortium of pharmaceutical companies led by Regeneron (and including also AbbVie, Alnylam, AstraZeneca, Biogen and Pfizer) will afford by 2020 the complete exome sequencing of half million UK’s citizens that voluntary adhered to the UK Biobank providing their biological samples, together with many other health and life style information (see here for more details). These data will allow to gather an extensive picture of the state of health or disease to be used to accelerate the discovery of new medicines. After one year of exclusive use for the six companies of the consortium (each of one contributing to the costs of the project with € 10 million), the sequencing data will be made available also to independent research.

AI to support diagnosis

Another main field of application of artificial intelligence is expected to be in supporting diagnosis. The medical imaging and diagnosis segment of the AI’s market is also expected to grow 40% CAGR, to surpass $ 2.5 billion by 2024. China should be the country evolving faster in this direction: application of AI to medical diagnosis is the first phase, to be implemented by 2020, of the government’s plan “China’s AI Awakening”. According to MIT Technology reviews, AI should help reduce the impact of the very low number of medical doctors in China (1.5 for every 1.000 inhabitants).
The great capacity of data analytics makes machine learning and deep learning algorithms able to directly learn from the huge amount of diagnostic images stored into clinical repositories. This knowledge will increasingly support the human decision within the diagnostic process. The FDA recently approved OsteoDetect, the first computer-aided detection and diagnosis algorithm that analyses two-dimensional X-ray images for signs of distal radius fracture and marks the location of the fracture on the image. The FDA also approved an AI-based medical device to detect greater than a mild level diabetic retinopathy in adults affected by diabetes. Similar applications are expected to be soon available to analyse also images from CT and MRI.

Data-driven platforms of cure

The adoption of artificial intelligence is central also to develop new and more patient-centric modalities to ensure provision of healthcare services. Web-based platforms to access such data-driven services should be the key, according to the report of EY, for pharmaceutical, biotech and medtech companies to gain access to the real-world data which are increasingly representing an important pillar of drug development and regulatory evaluation in the post-marketing phase.
Platforms of cure might also support a better definition of fair value for certain products or technologies on the basis of their perception by end users, the patient-consumers. The increasing availability of disease-specific platforms, for example focused on diabetes, may also contribute to keep better under control the increasing costs of public health expenditure.
Apps for smart devices might also represent a new tool to improve compliance to therapy, even if the results of the MediSAFE-PB trial recently published in JAMA Internal Medicine are not encouraging. The 12-weeks long study recruited the 5577 participants with uncontrolled hypertension through an online platform, 412 of which met the inclusion criteria and were instructed to download and use the Medisafe app, which provides reminder alerts, adherence reports and optional peer support. According to the authors, at the end of the study patients randomised to use the smartphone app had a small improvement in the self-reported medication adherence but no change in systolic blood pressure compared with controls. An not encouraging result to start with, even if the approach is patient-friendly and should thus encourage adherence to treatment and reporting. You can read some experts’ opinions on the unexpected outcomes of the Medisafe study in the article published by MedCity News.

Artificial intelligence for the supply chain

Logistics is another field where artificial intelligence may greatly support the activities of the entire pharmaceutical supply chain. DHL, for example, run together with Accenture a pilot project to evaluate the impact of the blockchain technology on the pharmaceutical supply chain. This technology shall not only support a more efficient management of contracts and payments, but it is also expected to greatly enhance the security level in shipments of medicinal products, thus helping in the prevention of counterfeiting. The serialisation prototype developed under the pilot included six nodes in different geographic areas to track medicinal products along the entire supply chain. The technology can handle more than 7 billion serial numbers and 1.500 transactions per second, according to the study.

India is playing a leading role in the implementation of blockchain technologies to better manage several different processes. The south-eastern Indian State Andhra Pradesh is at the center of the experimentation of the new model, being the first state in India to adopt blockchain for governance. In 2016, the local government launched the project to build the fintech city Visakhapatnam (“Vizag”), a port city that, according to Forbes, is emerging as the country’s blockchain hub. Vizag will also host the development center of Shivom, a blockchain-enabled healthcare platform that aims to be the largest unique genomic and healthcare research hub on the planet. The company signed a Memorandum of Understanding with the Government of Andhra Pradesh in order to sequencing and analysing the genome of its 50 million inhabitants as a measure to revamp the State’s healthcare system and provide more personalised care. The project might represent the first step toward a new model of healthcare, which would fully exploit the predictive power of genetic data to shift healthcare systems from being reactive toward a more preventive approach. “Our partnership with Shivom explores the possibilities of providing an efficient way of diagnostic services to patients of Andhra Pradesh by maintaining the privacy of the individual data through blockchain technologies,” said J A Chowdary, IT Advisor to Chief Minister, Government of Andhra Pradesh.

The challenges for pharmacies

Pharmacies are them too called to face the new challenges coming from the extensive adoption of artificial intelligence. According to The Royal Pharmaceutical Society, just selling medicines is no more a vital business model, and pharmacists should focus to enter the new patient-centric model of cure providing new services to costumers and helping them to achieve compliance to treatment or enhance their life style. Pharmacists should then transform into true health managers, according to The Medical Futurist, that support the patient along all steps of its trip into the disease.
This includes also the possibility to directly 3D-printing medicines on demand within the pharmacy, or provide some low level consultation services from remote with the help of AI algorithms (see also the article published by Forbes).

EU: The European cooperation on Health Technology Assessment

Giuliana Miglierini
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EU: The European cooperation on Health Technology Assessment

The process of Health Technology Assessment (HTA) is central to determine the fair, systematic, robust and unbiased evaluation of health technologies both on the medical, social, economic and ethical point of view. The process aims to provide patients’ access to innovative medicinal and medtech products while ensuring the best value for healthcare systems.
The European Commission adopted the draft text of the new HTA regulation on 31 January 2018. The text is expected to be examined and finally approved by the Parliament and Council of Europe by 2019, to then enter into force after three years in Member states. A further transition period of three years is planned from this date.

Four areas of cooperation

The proposal considers four possible different scenarios for cooperation in HTA, starting from the joint clinical assessments to be run on the most innovative health technologies. Joint scientific consultations will be the preferential tool for developers to seek advice from HTA authorities. These will be also involved in the identification of emerging health technologies, and might continue as well voluntary cooperation in other areas. Individual EU countries will continue to be responsible for assessing non-clinical (e.g. economic, social, ethical) aspects of health technology, and making decisions on pricing and reimbursement.
The proposal of the new regulation focuses its attention on the clinical part of the assessment, as it represents the common base shared at the global level for the evidence to be provided to competent authorities to reach regulatory approval (in the case of medicines as well as medical devices or diagnostics). The Coordination Group will be the central point for the coordination of all efforts under the provision of the new regulation.

Overcome the current duplication of efforts

The final outcome of the proposed regulation directly impacting on the pharmaceutical and medtech industries is an improvement of business predictability and a long-term sustainability of HTA cooperation with Member states, thanks to the convergence in HTA tools, procedures and methodologies, the reduction of duplicate efforts for HTA bodies and industry and the use of joint outputs.
Many initiatives to support HTA have been launched since the 1980s; the main actions at the European level are currently undertaken by EUnetHTA (the European network for Health Technology Assessment). The third action launched by the network for years 2017-2020 focuses on developing common assessment methodologies, piloting and producing joint clinical assessments and full HTA reports, and on developing and maintaining common ICT tools. But the efficacy of this project is undermined by the voluntary participation of different countries, leaving behind a still fragmented scenario, which is now addressed by the proposal of the new regulation.
Among issues to be solved in order to harmonise the modalities for HTA in the European Union are the differences in data and evidence requested by the different national authorities in charge of the procedure, which also use different methodologies to run the assessment. According to the Commission, this leads to an impeded and distorted market access, lack of business predictability, higher costs and negative effects on innovation. The already available tool of joint clinical assessments is still not widely used and adds a further level of duplication. Furthermore, according to the proposal, funding of HTA projects occurs on the short term, mining the long-term stability of the process.

Four scenarios for the impact assessment

Together with the proposal of the new regulation, the Commission also published the report of the Impact assessment run to estimate outcomes that might be expected under four different scenarios, starting from the baseline option 1 (no joint actions after 2020) to project-based cooperation on HTA activities (option 2), permanent cooperation on common tools, procedures and early dialogues (option 3) or, finally, permanent cooperation on common tools, procedures, early dialogues and joint clinical assessments (option 4).

Option 4 has been the preferred one, with integration of some elements of option 2 and some adjustments regarding transitional arrangements for Member states and progressive implementation of the product scope for joint clinical assessments. This approach has been considered to provide the best combination of effectiveness and efficiency in reaching the policy objectives, while respecting the principles of subsidiarity and proportionality, and it forms the base for the proposal of the new regulation.
The European Commission also launched between October 2016 and January 2017 an online public consultation on the initiative, those results are also summarised in the impact assessment report and were taken in due consideration during the development of the legislative proposal.

The comments from the Parliament’s subcommittees

In April 2018 the Committee on Industry, Research and Energy of the European Parliament published its draft comments of the proposal, highlighting the fact that “a reinforced cooperation would boost the efficiency and cost-effectiveness of industries and manufacturers involved in the healthcare sector and thus their competitiveness on a global scale”.
The Rapporteur Lieve Wierinck underlined the lack of a clear definition of the methodologies within the proposal, something to be better developed in the future. Top level scientific evidence should be used for the joint HTAs, is the suggestion; the Committee also approved the role of the Coordination Group and the use of mandatory uptake of joint clinical assessments and asked for a more structured involvement of patient organisations, industry and other stakeholders. A negative opinion has been issued on the possibility to include also medical device in the scope of the regulation, recommending their exclusion from the final version as national HTA bodies already have other useful tools to evaluate them.

The Committee on the Internal Market and Consumer Protection published its draft opinion on May 2018 (Cristian-Silviu Buşoi as Rapporteur). Proposed amendments include the possibility for certain Member States to start clinical assessments “even before the marketing authorisation has been granted by the Commission”. To avoid delays compared to the status quo, the process should be completed in any case by the time of the publication of the Commission decision granting MA. The Committee also proposed to take into account the methodological guidelines and evidence submission template developed by EUnetHTA and asked for a periodical revision of the methodological framework used for assessment in order to adapt it to scientific advances. Special features characterising certain technology (e.g. AMTPs) might also require a more specific clinical study design, which is already often accepted for the purposes of regulatory assessments. The methodology should thus be sufficiently flexible to include the acceptance of the best available scientific evidence at the time of the submission. The Committee also proposed that each Member state shall appoint to the Coordination Group at least one authority or body with expertise in medicinal products, one with expertise in medical devices and one for in vitro diagnostics. At the end of the transitional period, the identification of emerging health technologies in the field of medicinal products shall reflect EMA pre-notification prior to MA applications; the Coordination Group shall thus initiate joint clinical assessments according to this. A procedure is also suggested to allow developers to object in writing to the results of the approved joint clinical assessment report and summary report.

The Committee on the Environment, Public Health and Food Safety published in May 2018 its draft comments (Soledad Cabezón Ruiz as Rapporteur). Among main requests, the Committee underlines that a high percentage of marketing authorisations for medicinal products are not accompanied by a comparative effectiveness study and the fact “the high price of medicines, in many cases without these being of added therapeutic value, and the lack of new treatments for certain diseases” are among the main barriers to access.
The comments also contains the proposal to move towards a centralised authorisation system for medical devices based on safety, efficacy and quality. The transparency of the procedure should be guaranteed by the public availability of all data used for the HTA, including clinical data, studies, the methodology and the clinical results. “The highest possible level of public openness in scientific data and assessments will allow progress to be made in biomedical research and ensure the highest possible level of confidence in the system”, wrote the Committee, while the Commission’s proposal indicated the way of wide consultations with the interested parties. From this point of view, the Committee also asks that all “stakeholders involved (ndr. in HTA) are neither profit-making entities nor funded by technology developers”.
The Committee also suggests that the cooperation in the field of HTA may also cover areas such as complementary diagnosis, surgical procedures, prevention and health promotion programmes, information and communications technology (ICT) tools and integrated care processes. According its comments, the approval of the assessment should not be based on a simple majority (as proposed by the Commission), but instead on the consensus or, where not possible, by a two-thirds majority of Member states present. The conclusions of the joint clinical assessment report, asks the Committee, shall “include” (and not “be limited to”) the requirements indicated by the regulation and be based on the “best” available “clinical” evidence. The conclusions and all documentation supporting HTA shall be made public available on the common IT platform for HTA to be created at the European level. This also applies to any decision to withdrawn the application or to stop the assessment made by EMA. The Summary report of all assessed technologies should be included at the end of the procedure in a positive or negative list. These lists shall represent the reference for Member states to not duplicate efforts at the local level. The joint assessment should be reviewed at least every five years to update it to new evidence.

Questions to the European Parliament

Some written questions to the European Parliament on the draft proposal have been also presented.
Deputy Alfred Sant (S&D) asked information about how the Commission run the calculations in order to estimate the total costs involved in undertaking an HTA for a new medicine across EU Member States and the potential cost savings from a unified approach to HTA as recommended in its proposal. Mr Sant was also interested in better knowing the estimated extent to which delays in assessing a medicine or technology can be reduced through the introduction of a joint HTA assessment.
Deputy Roberto Metsola (PPE) asked if the Commission’s proposal will focus on the issue of having multiple national assessments for the same products that sometimes produce different results for patients and industry.

Answer to this last question was provided by Health Commissioner Andriukaitis, according to which the proposal is appropriate and proportionate to the problems identified in the impact assessment report, including duplication and divergent outcomes. The unique European framework proposed for joint clinical assessment of the most innovative health technologies should prevent duplications at the national level. “Harmonised rules will be developed on how clinical assessments are carried out. These rules are foreseen both for clinical assessments at Union level and for those assessments that have not been prioritised for assessment at Union-level and are therefore carried out at national level”, said Mr Andriukaitis. Member States shall also have the opportunity to cooperate, on a voluntary basis, on the non-clinical aspects of HTA.

Some examples at the national level

In France, taken as an example of country with well established procedures, policies for HTA and pricing and reimbursement of medicines are established by the Haute Autorité de Santé (HAS, see for example this presentation).
The benefit/risk evaluation that leads to MA is run by the Agence nationale de sécurité du médicament et des produits de santé (ANSM), or by EMA in the case of centralised procedures. After the opinion on HTA issued by the Transparency Committee of HAS, the final decisions on price, level of co-payment and inscription into lists are taken by the Ministry of Health.
All medicines have to be assessed by HAS on the base of medical evidence to be included in the positive list of reimbursed products, under a separate process with respect to price determination run by the Economic Committee for Health Products (CEPS). Assessment is renewed at least every five years for products listed as available in community pharmacies, or when new evidence is available.
Effectiveness, relative efficacy and healthcare need form the base to calculate price and reimbursement. Required data include results from randomised clinical trials or meta-analysis, tolerance data and pharmacovigilance. A discussion of comparators and therapeutic strategy is also requested. Reimbursement rates are linked to the effective benefit provided, ranging from important (65%) to moderate (30%) and mild (15%). Products showing an insufficient benefit are not included in the positive list. The assessment takes also into consideration how the new medicinal product can ameliorate the patient situation (on a five degrees’ scale) in comparison to already available therapeutics, in order to establish its relative value.

In Poland, the Agency for Health Technology Assessment (AHTAPol) is quite young, as it was established in 2005. It acts as an advisory body to support the Minister of Health in the decision-making process and is responsible for running HTAs, produce reports, and for the collection and dissemination of all information on the process, including methodologies to be used. AHTAPol structure has been developed under the Transition Facility 2005 Project financed by the EU Commission, that shall also contribute to future expansion of its capabilities and to training of its workforce.
The four main departments of AHTAPol (for a total of 40 permanent staff) are in charged respectively of HTA, international cooperation, economic analysis and monitoring costs of health services. Appraisal of HTA reports and issuing of the recommendations for the assessed technologies are under the responsibility of the Consultative Council, made of 8 members appointed for five years. AHTAPol Director presents the final recommendations to the Minister of Health. Assessment reports are published on the AHTAPol website, with abstracts available also in English.

Greece greatly suffered the effect of the 2015 economic crisis, resulting in the deterioration of its public healthcare system. Since then, the country is undergoing a profound programme of reforms with the aid of the European Union and other international institutions. Several actions are already in place also to strengthen the capacity of national competent authorities to perform HTA’s activities.
A WHO/Europe mission, for example (see here for more information), took place in Greece in 2017 under the Strengthening Capacity for Universal Coverage (SCUC2) initiative with the aim to assess previous actions, provide technical and legal support to the authorities on the proposed new legislative framework, and identify short- and medium-term objectives to create a suitable environment for HTA-based decision-making.
The SCUC initiative aims to support authorities in the move towards health universal coverage and the transformation of the Greece’s medicines reimbursement system. During the meeting the parties agreed on future steps in HTA policy implementation, related mainly to developing national capacities to run the assessment. The discussion saw the participation of Greece’s Ministry of Health, members of the HTA Working Group and its legal team, the director of the National Organisation for Medicines (EOF), members of the Negotiating Committee and the current Positive List Committee, and the director of the Institute of Pharmaceutical Research and Technology (IFET). Technical support and inputs to the discussions and development of the legal framework was provided by experts from Portugal’s HTA agency, INFARMED, being part of the WHO team.

The Joint Declaration on Pharmaceuticals in the Environment

Giuliana Miglierini
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The Joint Declaration on Pharmaceuticals in the Environment

The European Federation of Pharmaceutical Industries and Associations (EFPIA), PGEU representing European community pharmacists and EPSA on behalf of European Pharmaceutical Students are among the associations who signed the Joint Declaration on Pharmaceuticals in the Environment.
The new initiative highlights once again the importance to achieve a constructive dialogue with the European Commission, in order to safeguard the environment from the pollution derived by the presence of medicines and avoid issues for public health. The major source of pharmaceuticals in the environment, according to the Eco-Pharmaco-Stewardship (EPS) initiative, is represented by patient excretion following use, followed by a smaller contribution due to emissions from industry during the manufacture of medicinal products.

The importance of a balanced approach

The Associations who signed the Declaration ask the European Commission a balanced approach while working at the development of the new EU-wide strategy on pharmaceuticals in the environment.The industrial and technical parties, from their side, are fully committed to interact in an open and constructive way to reach this goal. Any new environmental-based measures, states the Declaration, should be clearly justified and “guarantee patient access as well as access to the demonstrated benefits that medicines bring to public health”. The new European strategy is expected to be announced by the Commission before the summer, according to Politico.

The actions taken by the industry and its partners

The pharmaceutical industry is not new to initiatives aimed to reduce the burden of pharmaceuticals in the environment. An example is the Inter-Association Initiative on Pharmaceuticals in the Environment (IAI PIE) that groups the Association of the European Self-Medication Industry (AESGP), the European Federation of Pharmaceutical Industries and Associations (EFPIA), and the European Generic and Biosimilar medicines association (EGA). Its first action – the Eco-Pharmaco-Stewardship (EPS) initiative – addresses the roles and responsibilities of all parties involved in the medicines’ life cycle, including public services, industry, environmental experts, doctors, pharmacists, and patients.
Three pillars have been identified as key areas of attention for the pharmaceutical industry. First of all, the identification of the potential environmental risks of existing and new active pharmaceutical ingredients. This should be paralleled by an efficient management of the manufacturing effluents, that should be based on available best practices in order to minimise the risks for the environment. The third pillar is represented by the refinement of the existing environmental risk assessment (ERA) process for medicinal products to ensure that it remains up-to-date and relevant.

Not less important is the need to increase awareness of the wide public. The Declaration refers to the example of the #medsdisposal educative campaign, a collaborative multi-stakeholder effort endorsed by EIPG, aiming to ameliorate the correct disposal of unused and expired medicines. Flushing medicines down the toilet or pouring them in the sink is still the often preferred way to discharge medicines and it represents 8-10% of the pharmaceuticals into the environment, according to the Declaration. Many EU’s countries have put in place special disposal schemes to prevent this form of pollution. The suggestion made by the Declaration to all interested stakeholders is to join and endorse the #medsdisposal campaign, by contacting the email address medsdisposal@gmail.com.

The Declaration also refers to the 2011 WHO’s report “Pharmaceuticals in Drinking-water” to state that there is currently “no evidence of harmful concentrations of active pharmaceutical ingredients in the European drinking water”.
WHO’s analysis highlights that there is currently lack of routine monitoring programmes to test drinking-water for pharmaceuticals, as is the case for regulated chemical and microbial parameters. The available data mainly come from ad hoc surveys or targeted research projects. The observed concentrations of pharmaceuticals in surface, groundwater and partially treated water are typically less than 0.1 μg/l, while in treated water are generally below 0.05 μg/l. WHO also asked for more systematic studies to better understand the transport, occurrence and fate of pharmaceuticals in the environment, on the basis of the standardisation of protocols for sampling and analysis.
The Declaration also recalls the action taken by the European Healthcare Distribution Association (GIRP) for the correct disposal of medicinal products through direct involvement of healthcare distributors in the national waste management systems. CED, PGEU and EPSA, representing healthcare professionals (dentists, community pharmacists and pharmaceutical students, respectively), are also offering their members education and exchange of best practices for the safe, rational and effective use of pharmaceuticals.

The suggestions of the European Environmental Agency

The European Environmental Agency (EEA) run a workshop in 2010 those results have been published in the document “Pharmaceuticals in the environment”, also cited by the Declaration.
This document suggested several proposals for action, among which are the definition of environmental quality standards for pharmaceuticals, and an environmental risk assessment of human pharmaceuticals to be part of the risk/benefit analysis during the authorisation process. Further points include consideration of plant protection products or industrial chemicals on eco-evaluation (similarly to biocides) and the development of possible risk mitigation measures as part of the authorisation process. 
EEA also suggests to classify all pharmaceuticals according to their environmental hazardousness and to introduce incentives for green pharmacy. Research should focus on better methods for eco-efficient synthesis; harmonisation across UE countries would also be needed on how to dispose unused pharmaceuticals.
According to the Environmental Agency, pharmaceutical waste should always be incinerated; wastewater treatment (for example with activated carbon, advanced oxidation or UV) should be considered to destroy unavoidable remnants of active substances and metabolites.
A better set of data on long-term effects and fate of pharmaceuticals in the aquatic environment are also needed, a goal that might benefit from the collection of currently not classified data generated by research or authorisation processes, which should also be made publicly available in an EU database. Antibiotics and other pharmaceuticals potentially dangerous for the environment should be object of priority actions. EEA also suggested to include the environmental effects into the ‘pharmacovigilance’ concept, with relation to the understanding and prevention of adverse effects; post-marketing environmental monitoring might be applied to surface, ground and drinking water and biota, as well as data on sewage treatment sludge to distinguish between degradation and elimination/removal of pharmaceuticals and on the potential for microbial resistance of pharmaceuticals.

Redistribution of the UK centrally authorised product portfolio

Giuliana Miglierini
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Redistribution of the UK centrally authorised product portfolio

The European Medicines Agency (EMA) has published a document describing the process of redistribution of the UK centrally authorised product (CAP) portfolio as a part of the preparation to the Brexit. The process involves the reallocation of UK rapporteurs and co-rapporteurs from EMA’s Committee for Medicinal Products for Human Use (CHMP), Pharmacovigilance Risk Assessment Committee (PRAC), Committee for Advanced Therapies (CAT) and Committee for Medicinal Products for Veterinary Use (CVMP). The procedure has been endorsed by EMA’s Management Board at its December 2017 meeting and has been published in April 2018.

The redistribution process

From 30 March 2019 the United Kingdom will become a ‘third country’, thus the local regulatory authorities MHRA (human medicinal products) and VMD (veterinary products) will no longer be able to act as Co-rapporteus in centralised regulatory procedures.

EMA already started to redistribute current UK’s tasks taking into account the diverse expertise of the other components of the European regulatory network, the workload and the legal basis associated with each medicine. Furthermore, clusters of products with the same international non-proprietary name (INN) and/or belonging to the same marketing authorisation holder (MAH) will be allocated to a single rapporteur in order to facilitate review of post-authorisation procedures. According to the established procedure, once the MAH and the new (Co)-Rapporteur have been informed about the change, this last one will start to receive all relevant knowledge from UK, but it will assume full responsibility for the re-allocated products only starting from 30 March 2019.
Each national competent authority (NCA) will be in charge of a maximum number of products (ceiling), adjusted for each role and based on the number of products to be allocated. “Newer” member states who have indicated in surveys run by EMA the wish to increase their involvement in managing generic and hybrid medicinal products will receive reallocation of UK CHMP Rapporteurships for these products, that are also associated with a lower workload in the post authorisation phase.
All other products (i.e. full applications and biosimilars) are reallocated from UK to the current Co-Rapporteur to a maximum of 10 medicinal products per national competent authority. Remaining products, explains EMA, are allocated based on the current expertise in the network (as CHMP Rapporteur, based on ATC code distribution) and the workload associated to each medicine in post authorisation.

The UK CHMP Co-Rapporteurships are allocated to the Peer Reviewer involved in the initial application for marketing authorisation to a maximum of 15 medicinal products per NCA, or on the basis of the current expertise within the network if a Peer Reviewer has not been appointed.
The UK PRAC Rapporteurships for generic medicinal products are automatically allocated to the PRAC Rapporteur of the reference medicinal product. For all other types of medicinal products, allocation is based on clusters of products with the same INN, current expertise in the network and the workload associated to each medicine in post authorisation, for a maximum of 5 medicinal products for each NCA.
Assignment of new CHMP/CAT/PRAC (Co)-Rapporteurs for human medicines will also follow the same general principles, as well as the one for veterinary medicines.

The industry associations are also preparing for a smooth transition

The association representing the pharmaceutical industry are also working to optimise all actions needed to afford a smooth Brexit transition. EFPIA, the Federation of the Pharmaceutical Industries and Associations, published in December 2017 its list of priorities to be faced both on the European and UK’s side of the Channel.
These include the alignment of the pharmaceutical regulations, cooperation and mutual agreement between the European Union and UK, the availability of a straightforward immigration system to allow UK-based pharmaceutical companies to continue employing the best talents, the maintenance of scientific research collaborations in life sciences as a tool to attract global investments, the availability of equivalent standards of intellectual property and a comprehensive agreement to ensure maximum alignment between EU’s and UK’s pharmaceutical laws and guarantee market access and supply of medicines.

In March 2018 many associations representing the European and British life science industry (AESGP, ABPI, BIA, BGMA, EBE, EFPIA, EUCOPE, EuropaBio, Medicines for Europe, PAGB, Vaccines Europe) approved the terms of the transition period agreed between the UK Government and the European Union. A decision that gives companies a more reliable time framework to prepare for the final transition. “At the current status of negotiations, we continue to advise our members to prepare for every scenario and ensure that they have the right plans in place”, wrote the pool of associations in their statement.

Bulgaria: Access to medicines at the center of the Bulgarian presidency of the European Council

Giuliana Miglierini
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Bulgaria: Access to medicines at the center of the Bulgarian presidency of the European Council

The Bulgarian presidency of the Council of Europe saw the organisation, on 6 March, of the “Conference on Options to Provide Better Medicines for all European citizens”: an occasion to deeply discuss important issues regarding rapid access to therapies, such as how dealing with medicines shortages.

A question to the European Parliament

This specific topic has been declared a priority of the Bulgarian presidency and it has been object of a question for written answer on parallel trade to the European Parliament made on March 1st by deputy Andrey Kovatchev (PPE). According to Mr Kovatchev, in early 2018, patients’ organisations in Bulgaria reported that around 60% of the medicines imported into the country were re-exported to other European markets. The Bulgarian deputy thus asked the Commission for a new analysis of the reasons for the shortages of medicines and the impact of parallel trade, the introduction of a pan‐European system for monitoring movements of medicines along the supply chain and the establishment of an electronic EU register of prescriptions.
The answer to the question was provided on 25 April by EU’s Health and Food Safety Commissioner, Vytenis Andriukaitis, who declined any further analysis of the issue claiming that shortage of medicines has been already widely studied and discussed. The Commission, wrote Andriukaitis, is currently working to draft the final report based on the 2017 questionnaire on the measures implemented by the Member States for appropriate and continued supplies of medicines, that will be followed by an expert meeting aimed to identify and share the best practices to ensure continuity of supply and restrict parallel trade.
Commissioner Andriukaitis also rejected the possibility of a pan-European system for monitoring medicines, as a similar project is already in place and involves 22 Member States with the final goal of a Digital Service Infrastructure for the cross border exchange of electronic prescriptions and short forms of electronic health records. The first exchange of data between a limited group of countries is expected to start in 2018, to be then expanded in 2019. “This system will allow for medicinal prescriptions to be issued and transmitted electronically for citizens travelling inside the EU; it does not however foresee a central register for storage of ePrescriptions”, wrote Mr Andriukaitis in his answer.

The main outcomes of the Bulgarian presidency’s Conference

“Medicinal products are specific commodities and the trade activities performed with them, and the control over shortages of medicinal products should be regulated by sustainable solutions” is the key message emerged from the Conference organised by the Bulgarian presidency.
The four panels of the Conference examined different aspects related to fair access to therapies. At the base of pharmaceutical shortages is the principle of proportionality, that should guide every new legislative act. “This is where law and fact become intertwined. Application in practice can be challenging….”, explained the representative of the Council Legal Service, Matthew Moore. Proportionality in the legislative action is governed by article 5 of the TEU and Protocol No. 2 on the application of the principles of subsidiarity and proportionality. Application of the principle, explained Mr Moore, can lead to annulment of national and EU regulations, thus its proper understanding is fundamental.

The application of the principle of proportionality to shortages on medicines in Spain has been illustrated by Ms. Belén Escribano Romero, Head of Department, Pharmaceutical Inspection and Enforcement Department at the Agencia Española de Medicamentos y Productos Sanitarios (AEMPS). In 2010 the Spanish law (Article 54.5 of RD 824/2010) introduced the requirement of a prior notification to the AEMPS for shipments of medicinal products of human use to other Members States. After a pilot phase, the notification system started to be fully operative in July 2012: wholesale distributors have to notify the Agency at least 3 days before the shipment departure through an electronic system; notification is required only for products whose lack may cause a healthcare problem. The current list includes 14 medicinal products and 38 pharmaceutical presentations. Data for the concerned products have to be updated by MAHs every 6 months; in case of a possible shortage, AEMPS notifies the wholesaler and customs inspectors to stop the shipment, explained Ms Escribano Romero. Only 11 shipments (2% of total) were not allowed in the period 2012-2017; the number of shortages due to parallel trade decreased in Spain from 103 in 2007 to 11 in 2017.

The EU Commission’s questionnaire to Member States on the legal obligations and the  proposed measures received up to now a feedback from 23 countries, said Agnès Mathieu-Mendes, Deputy Head of Unit B4 of the DG Santé. Export restrictions are legitimate, according to the European Court of Justice, “in cases where parallel trade would effectively lead to a shortage of medicines on a given national market”. According to Ms Mathieu-Mendes, such measures might be based on negative lists of medicines, to be periodically revised and that do not include non-justified, large amount of products.

The industrial position was illustrated by the representative on the European Association of the Euro-Pharmaceutical Companies (EAEPC), Oliver Luksic, speaking of about 120-140 million estimates for parallel distributed medicines packages in Europe. According to Mr Luksic, parallel distribution is run according to GDP and GMP requirements and it is thus safe. Repackaging companies are at all effects considered MAHs. Parallel trade also allow to achieve lower prices, with more than € 500 million direct savings per year and indirect savings much higher, said Mr Luksic. Export restriction might deserve a negative real effect on the medium/long term, was the opinion of the EAEPC representative, as the result of negative price effects. A more effective mean to regulate the process of parallel trade, according to Oliver Luksic, would see the full implementation of the Public Service Obligations (PSO) by both wholesaler and MAHs.

The future of the European pharmaceutical industry

The main challenge, according to the Director General of Medicines for Europe, Adrian van den Hoven, relates to the need to provide answers to the ageing of population. Over-65 people currently represent 18,5% of the EU-28 populations, with estimates to reach 28% by 2050; this trend correlates to a corresponding increase in the prevalence of chronic diseases. Generic medicines currently cover 62% of the dispensed ones and represents a cornerstone of sustainability, thanks to the € 100 billion less spending achieved through generic competition. Biosimilars are expected to follow a similar trend of development, even though their market penetration is still far behind. Medicines for Europe also support the new concept of “value added medicines”, based on the use of known molecules to generate new products through drug repositioning (to treat new indications), reformulation (to develop new delivery systems) and availability of complex combinations (to allow new regimens of treatment).

The concept of repurposing towards new indications may offers important opportunities also for Olga Solomon, Head of DG Santé Unit B5, who highlighted the new holistic regulatory approach to facilitate early access to medicines. But repurposing, she commented, often suffers from a certain industry’s reluctance to include new indications. According to Solomon, this might be addressed by improving the knowledge of non-industry organisations and academics about the regulatory framework, a mechanism to provide advice or support on data quality and by bringing stakeholders together on a platform.
As for the Supplementary Protection Certificates (SPC), Solomon said that the DG Grow is assessing the possibility of a “unitary” SPC title, updating the scope of the EU patent Bolar and research exemptions and introducing an SPC manufacturing waiver.

Scientific advances and unmet medical needs are the key drivers of pharmaceutical innovation, but governments need to put in place strong incentives, rapid access to market and a stable pricing environment to facilitate the activities of R&D-focused pharmaceutical companies, said on behalf of EFPIA Boris Azaïs, Director of Public Policy at MSD. The roadmap to be follow to achieve the goal is similar to the one used to progressively develop and use innovative treatments for HIV and HCV. A roadmap that faced many failures, as demonstrated for example by the 123 candidates that failed clinical trials for Alzheimer’s disease since 1998 compared to the only 4 new medicinal products approved by the FDA in the same period. Neurological disorders together with cancer, immunological and infectious diseases are the main areas of investments in R&D and innovation.

Tools to provide early access

The term ‘benefit’ doesn’t necessarily have the same meaning for HTA and regulatory approvals, explained Stefan Lange, Deputy Director at the Institute for Quality and Efficiency in Health Care (Germany), commenting the different priorities to be taken into account during the two types of evaluations.

Various special programmes have been developed by the regulators to facilitate research and development and early access, e.g. the EMA Early Access Toolbox illustrated by the Agency’s Head of Human Medicines Evaluation Division, Zaide Frias. The number of parallel advises greatly increased since 2015, according to Ms Frias, with a level of alignment raging from 77% (with respect to the population considered in the studies) to 44% (with respect to the choice of the comparator). Artificial intelligence and new technologies such as wearables devices and smart home technologies today pose new challenges to the regulators and are changing the scene of pharmaceutical development; digital transformation will affect also regulatory activities, explained Zaide Frias.

The delicate limit between the action of regulators and the affordability of prices of innovative medicines has been explored by Yannis Natsis, Policy Manager, Universal Access & Affordable Medicines at EPHA. According to him, the key points to be addressed are the signals sent by EMA to the market, the position of the Agency towards imitation and over meaningful innovation, priorities posed by regulators to safeguard competitiveness of a business sector over public health needs and the relationship with pharmaceutical companies. EPHA asked EMA to be less dogmatic and defensive, to encourage a dialogue with the critical voices on all issues, to stop hiding behind the legislation while enforcing existing tools properly, to prevent further orphanisation of pharma regulation and to discourage abuse, overuse and misuse of incentives by manufacturers. A proactive position on issues of transparency and independence are other points requiring a major attention by the Agency, according to Natsis, as well as a better collaboration with the FDA and HTA bodies and actions intended to break down silos between national medicines agencies and Health Ministries.

The main grey issues linked to early access have been exposed by Josef Probst, Director General of the main Association of Austrian Social Security Institutions, who remembered the Council conclusions on strengthening the balance in the pharmaceutical systems highlighting concerns about very high and unsustainable price levels and the not always clear added value of some innovative products. No evidence of improvement in overall survival or quality of life was found at the time of MA for 39 of the 68 oncological indications authorised by EMA in the period 2009-2013, a number decreased to 33 after three years from the MA, said Dr. Probst. Just 33% of the 72 trials for market authorisation of cancer drugs in the period 2009-2013 were run against an active comparator, he added, while 35% were placebo controlled, 22% referred to add-on therapy and 10% had no comparator. The representative of payers also indicated that just 18% of the products which received EMA conditional approval in years 2006-2014 offered an advantage, another 18% were considered possibly helpful; judgement has been reserved in 28% of cases, while 27% of products were found not acceptable and 9% “add nothing new”.

How to achieve a better accessibility

Some of the many cases of massive overcharging of drug prices have been illustrated by Andrew Hill (Department of Translational Medicine, University of Liverpool, UK) on the basis of the initial prices of the active pharmaceutical ingredients used. The phenomenon involves also some generics medicines, said Dr Hill, those analysis indicated that almost all medicines are very cheap to manufacture. The suggestions advanced by the expert included the checking of prices and overcharging by countries, and the update every two years of the lists of drug costs and prices, in parallel with updates of the list of essential medicines. Dr Hill also suggested countries to buy all generic drugs at close-to-cost prices, maximising their use in national treatment campaigns. It would also be important to identify high quality generic suppliers and to act proactively to induce price reduction by a re-evaluation of the cost-effectiveness of all patented drugs vs. cheap generic alternatives, he said. Finally, according to Andrew Hill, if companies refuse to lower prices, countries might use TRIPS flexibilities to ensure access through compulsory licenses, personal importation and patent challenges.

Governments should know the actual numbers related to drug pricing and negotiate with pharmaceutical companies according to actual (not inflated) costs, added Fernando Lamata, representing the Association for Fair Access to Medicines, and ex-Secretary General of Health of Spain and ex-Regional Minister of Health of Castilla-La Mancha. Dr Lamata discussed the concept of value-based price vs. fair and sustainable price, this last one based on transparency of R&D costs and return on investments. Joint procurement, and the possibility of considering compulsory/mandatory licensing or manufacturing through private non-profit companies or public companies, as well as strengthening industry-independent EMA and HTA evaluations, are other suggestions advanced by Fernando Lamata.

EU Commission’s report on the off-label use of pharmaceuticals

Giuliana Miglierini
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EU Commission’s report on the off-label use of pharmaceuticals

The marketing authorisation of a medicinal product specifies the approved indications and terms of use (e.g posology), which are reported in the Summary of Product Characteristics (SmPC) and in the Patient Information Leaflet. Any use of the product different than the approved ones thus falls in the category of “off-label use”. A different indication, a different dosage, dosing frequency or duration of use, a different method of administration, or use by a different patient group are all examples of off-label use of medicines.
The European Commission has published the report “Study on off-label use of medicinal products in the European Union”, which offers a deep analysis of practices for the off-label use of medicinal products for human use across Member States and describes possible future tools to regulate this sector at a national level.

The paediatric population is the main target

The phenomenon of off-label use interests all European countries, with marked variations in prevalence within a single country on the basis of the methodology used and the population studied. The team of experts that wrote the document thus recognises the difficulty to make a comparison between the various EU Member States.
It might be not surprising that off-label use in Europe refers particularly to the paediatric population, since the development of targeted medicines for this age group is relatively recent. Orphan diseases are another main target, as well was elderly patients and pregnant women, but less information is available for the two last groups.

The analysis of the literature showed that the main clinical areas interested by the phenomenon are oncology/haematology, psychiatry and rheumatology, all characterised by unmet medical needs. The reported range of off-label prescription in the paediatric population is very wide both in hospital settings than in outpatient settings; a similar trend has been observed for the adult populations.

The driving factors

The marketing authorisation process and post-MA events (such as shortage of medicinal products and pricing and reimbursement) have all been identified by the study as the driving factors for off-label use of medicines. The better access of patients to (innovative) treatments and the fulfilment of their medical needs, especially in cases where no other options are available, and a potential economic advantage (provided that economic reasons are not prevailing) are other favourable elements that support the phenomenon.
Industry can benefit of only limited incentives to extend the labelling of existing medicinal products, especially for off-patent products suffering the competition of generics and/or a low price, indicates the report. The current regulatory framework allows for one year extra market protection if a new indication is registered in the first eight years after the initial MA has been granted, and provided that the new indication brings significant clinical benefit over existing therapies. “However, off-label sales will continue without investment in such a new indication anyway”, says the report.

Many stakeholders also indicated during the survey the impact of the increasing requirements to obtain an MA and the time and costs needed to investigate a new indication. From the healthcare professionals (HPCs) perspective, off-label prescription is sometimes inevitable and it might be reinforced by the pressure of patients asking access to a certain therapy. The global picture is quite complex and highly variable in time along the life cycle of the medicinal product, with many different driving factors that might interact with one another in an hard to evaluate contribution, is the conclusion of the Commission.

The legal framework

Is it off-label use of pharmaceuticals prohibited or regulated by the law? Sentence T-452/14 (Laboratoires CTRS vs Commission, paragraph 79) of the European Court of Justice answered the question, confirming that “off-label prescribing is not prohibited, or even regulated, by EU law” and that “there is no provision which prevents doctors from prescribing a medicinal product for therapeutic indications other than those for which a marketing authorisation has been granted”.
The analysis made by the EU Commission’s document keeps clearly separated the regulation of medicinal products from their effective use in the medical practice. Off-label use of medicines is theoretically prohibited according to article 6(1) of Directive 2001/83/EC, establishing the need of a marketing authorisation to sell a new product in the European market. The paradigm of quality, efficacy and safety and the benefit/risk assessment are at the base of the pre-clinical and clinical development faced by the pharmaceutical industry to finally obtain the MA from EMA or national competent authorities. But, as already said, the entire development is targeted to a specific indication (or a limited pool of indications) and might not support the same requirements of safety, quality and efficacy and benefit/risk ratio with respect to off-label use.
This notwithstanding, the higher prevalence of off-label use in the paediatric population is somehow recognised as a concept by the EU pharmaceutical law – indicates the report – under recital 2 of the Paediatric Regulation (1901/2006/EC) and the pharmacovigilance provisions in Directive 2010/84/EU. Also the Orphan Medicinal Product Regulation (141/2000/EC) is expected to contribute decreasing the extent of off-label use of medicines, even if according to the Commission it is still difficult to evaluate the real impact of these regulations.

A complete different thing is the daily medical practice, where medical doctors are free to prescribe medicines according to the principles of knowledge and belief. The off-label prescription becomes, from this point of view, just a step of the relationship between the patients and its doctors, explained the report. Furthermore, each Member State is free to organise its internal healthcare system and is responsible for the definition of health policies and the delivery of the related services (Article 168 (7) TFEU). Healthcare professionals prescribing off-label medicinal products are subject to both EU’s product liability and professional liability legislations if the prescription is inappropriate. Ethical and professional standards and codes of conduct are also governing the action of HPCs, which might be sanctioned by disciplinary boards. In some instances the criminal law might also apply.
Finally, reimbursement of off-label prescribed medicines depends upon the specific national health insurance legislation of each Member State. Reimbursement is also at the center of many cases discussed by national courts, those results indicate that additional requirements may apply, including the limitation to life-threatening or severe conditions and the absence of alternative treatment options.

The national frameworks are very different

The exercise run by the European Commission also analysed the national frameworks governing off-label use in different Member States, resulting in a very fragmented picture. In France and Hungary, for example, prescribers or their organisations have to ask for permission to prescribe a product off-label under the legal framework of the “temporary recommendations for use (RTU) scheme”.
Reimbursement in France and Italy is allowed also when on-label, authorised or not strictly identical alternatives exist. Great Britain introduced in 2013 the General Medical Council Guidance (Good practice in prescribing and managing medicines and devices) to support the choices of prescribers. In The Netherlands off-label prescription is only allowed if the relevant professional body has developed protocols or professional standards with regard to that specific off-label use. HPCs have also to register for what intervention the patient has given its informed consent.
Many EU Member States do not have specific policy tools to guide off-label use, and in many instances the practice is seen as something pertaining prescribers rather than the regulatory or healthcare system level.

The options for the future

The study of the EU Commission suggests that the so-called ‘soft approaches’, providing guidelines and collecting practical evidence on off-label use, might represent the most appropriate tool to find a wide support among stakeholders. The survey also identified the possibility to include other evidence than the industry-based one to support off-label indications; randomised controlled trials for the marketing authorisation of off-label indications might represent an option, as well as evidence from monitoring patient cohorts, data from routine patient registries and from reporting adverse events.
General advice on off-label use provided to Member States might be useful to guide the development of national guidelines on the basis of a common ground. A better incentives framework might be addressed to the pharmaceutical industry to improve the registration of new indications, dosing or formulations for existing products. The expert meeting organised by the Commission found agreement in asking prescribers to apply with each Member State’s competent authority for the permission to prescribe off-label. This procedure would allow for a national evaluation of the benefit/risk ratio of off-label use.
Another critical point to be addressed is represented by the possible different reimbursement for off-label products and on-label competitors. Treatment guidelines published by professional bodies at the national level and improved patient information, preferably in the form of individual messages to patients provided by HCPs together with easily accessible online and printed information, have been identified as the main tools to better communicate these themes to healthcare professionals and patients.

Morocco: The opportunities for the pharmaceutical industry

Giuliana Miglierini
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Morocco: The opportunities for the pharmaceutical industry

Morocco is an emerging player in the global pharmaceutical market, even if its domestic industry has a long tradition. The stable political framework characterising the kingdom and its central localisation in the Mediterranean area, connecting Sub-Saharan Africa, Middle East and Europe, may support Morocco to achieve a further consolidation of the pharmaceutical and healthcare sector in the upcoming years. The country is part of the Arab Maghreb Union (AMU), which comprises also Algeria, Tunisia, Mauritania and Libya.
An ambitious health insurance program was launched by the Moroccan government, with the objective to cover 90% of the population by 2021.

A constantly increasing pharmaceutical market

Morocco’s healthcare spend has reached $ 6.15 billion in 2017, with an increase of +5,1% compared to the previous year. The pharmaceutical market has also evolved positively, reaching $ 1.48 billion sales in 2017 with forcasts of $ 1.9 billion in 2021 at a yearly expansion of 6.7% CAGR (data BMI Research, Morocco Pharmaceutical and Healthcare sector report, Q3 2017).
According to this report, in 2016 the prescription medicines represent 70.9% of the whole market, around $ 993 millions. Patended medicines represented 41.2% of the total market and 58.1% of the prescription one, but this part would decrease in the coming years due to encouragement of generics and (very recently) biosimilars, because their prescription is strongly supported by Moroccan government. According to Business Monitor International (BMI) study, currently generics and biosimilars cover 80-90% of the public medicines market and only 25% of the private one. Also the OTC sector would undergo the same competition from generics, and is expected to decrease its share up to 22.8% in 2026.
Currently pharmaceutical sales represent approx. 1,47% of Morocco’s GDP and 24.4% of the total health expenditure of the African countries.
Moroccan pharmaceutical industry ranks second in the continent and is also the second largest chemical industry of the country, after the phosphates’ one.
The sector draws about 400 million dirhams investments every year and more than 9000 direct jobs.
There are three professional associations in the country representing the different industries, i.e. the Moroccan Association of Pharmaceutical Industry (AMIP), Les enterprises du médicament au Maroc (LEMM) of multi-national companies and the Moroccan Association of Generic Medicines (AMMG).

The regulatory representation of pharmacists working in pharma industries and pharma distribution

All pharmacists practicing in pharmaceutical companies are represented by the COPFR, which stands for Conseil de l’Ordre des Pharmaciens Fabricants et Répartiteurs and can be translated as the Council of pharmacists working in pharma industry and distribution. This institution controls the access to the pharmaceutical profession by giving an adivisory opinion for pharmacist applications in order to join pharmaceuticals as well as for the creation, expansion or modification of pharmaceutical establishments.
The COPFR has two main missions. The first one consists in the scientific role: the COPFR has to give a support to pharmacists working in pharma-industry and pharma-distribution by setting up a training plan and scientific seminars. The second mission is the disciplinary role, by ensuring compliance with regulations, ethics and deontology.
About 300 pharmacists are referenced in the pharmaceuticals including industries and distribution. They hold different positions and responsibilities. They supervise the pharmaceutical acts (control of raw materials, packaging materials and finished products, production, storage, release, …).

A long tradition in pharmaceutical manufacturing

The local pharmaceutical industry sees both domestic companies, such as Cooper Maroc (founded in 1933 as a subsidiary of Cooper Melun France), Maphar (now part of the French Eurapharma CFAO Group), Sothema (founded in 1976 and manufacturing inter alia sterile products and antibiotics) and Laprophan (founded in 1949, the first Moroccan laboratory to have an R&D center), as well as subsidiaries of foreign multinational companies such as Sanofi Maroc. The total production capacity counted 46 different sites in 2016, manufacturing approx. 425 million units.

According to AMIP, the local pharmaceutical production covers 65% of the internal pharmaceutical market, while 10% is intended for export. The great part of active pharmaceutical ingredient are imported from abroad, says BMI.
As reported by the Association of the Pharmaceutical Industry, the Moroccan National Laboratory for the Control of Medicines (LNCM) has been certified both by the World Health Organisation and the European Directorate for the Quality of Medicines, thus acknowledging for the quality of the production run under GMP conditions. But BMI reports that the Moroccan pharmaceutical production is still far from European standards, even if the government has assured about “its commitment to improving the country’s regulatory system”. New agreements were signed in May 2016 between the Moroccan government and local pharmaceutical associations in order to expand the manufacturing capacities on a national scale and to establish the kingdom’s first pharmaceutical clusters. Synergistic to this action should also be the announced reduction of regulatory approval times with respect to registration of new medicines.
The generics sector invests each year approx. 300 million MAD (15% of which in R&D activities), writes the local association AMMG on its website, and employs 3.500 people. The majority of generics medicines present on the Moroccan market are locally produced, while Africa and Middle East are the preferred areas of export (counting for 8% of the generics’ production).

The regulatory framework

Morocco is among the North African countries benefiting from a higher political stability, a liberal economy and an educated workforce; practically, all important elements in order to attract foreign investments. This is paralleled, in the pharmaceutical and healthcare areas, by the liberalisation of the capital stock of pharmaceutical companies and, from the regulatory perspective, from a reform that took place in 2006 aimed to improve the compliance to ICH recommendations and international quality standards for manufacturing of medicinal products.
Regulatory procedures are under the control of the Drugs and Pharmaceutical Directorate of the Ministry of Health. The latter is divided into three subdirections: firstly, the Division of Pharmacy (responsible inter alia of clinical drug evaluation, registration and pricing where appropriate); secondly, the Pharmaceutical sector monitoring department (e.g. scheduling inspections in order to establish GMP certificate) and finally, the LNCM which is responsible of the quality review of pharmaceutical documentations as well as of lab-testings.

The mechanism of the pricing of medicines depends on their status: innovative, generics or biosimilar. Prices of medicines have also been repeatedly reduced in the period 2010-2016, a possible element lowering the appeal of the country for foreign investors, according to BMI. A new price decree was adopted by government in December 2013 comparing ex factory prices of countries of reference (France, Spain, Portugal, Saudi Arabia, Turkey, Belgium, and the country of origin when it is different from the mentioned list)

The government also planned actions to reduce retail mark-ups and VAT for chronic illness medicines, and to improve the medicine supply chains, increase the number of qualified staff and facilities and promote the rational prescription of medicines, adds the report by BMI. Plans are also ongoing to eradicate the Hepatitis C Virus by 2030.

On another level and under the control of the Ministry of Health, there is also the Pasteur Institute of Morocco, devoted to basic and applied research and which provides expertise, biological analysis and advice not only to the administration, national, regional or international institutions but also to the pharmaceuticals. This Institute is also responsible for the manufacture, import, and distribution of some vaccines, serum and biological products for therapeutic use and diagnosis.

From another perspective, the Intellectual property protection is ensured by the free trade agreement with the US signed in June 2004 and the patent law issued in 2000, which complies with the WTO Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS). This law prevents the parallel import of patented products.

A stable reference framework

The ability to quickly adapt to the rapidly evolving scenarios and the deep knowledge of its international reference framework are essential, according to AMIP, to maintain the competitive position of the Moroccan pharmaceutical industry. From its website, the Association calls to an urgent effort to better delimit the economical boundaries of pharmaceuticals. According to Business Monitor International, the new Moroccan government is expected to continue pursuing the roadmap of reforms, to ensure a better access to healthcare services even if the total budget allocated by now (5.7% in 2017) is still lower that the level recommended by the WHO (12%).
The pharmaceutical and healthcare internal markets are also sustained by an increased shift of the population towards the middle class; furthermore, as for the great part of countries, the ageing of population is an increasing issue also for Morocco, especially in the urban areas. The Mandatory Health Insurance scheme introduced in 2006 for Moroccan citizens and provided by the National Agency for Health Insurance (ANAM) is aimed to allow broader access to healthcare service, but according to the World Bank in 2017 this measure still does not reach over 25% of Moroccans.

The new topics of IMI Call 14

Giuliana Miglierini
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The new topics of IMI Call 14

Better control of immune-mediated diseases, non-invasive imaging of immune cells, machine learning for drug discovery and advances towards better, more patient-friendly clinical trials are the topics of the new IMI calls for proposals. The deadline to present the project is 14 June 2018.
The call will provide a total budget of approx. € 167 million, € 84,92 mln of which will be covered by EFPIA companies and IMI2 Associated Partners and € 82,36 mln by IMI2 Joint Undertaking.
The interested companies and research centres can find all documents needed to apply – including the IMI Manual for evaluation, submission and grant award (version 1.6) – on the Participant Portal and the IMI2 Call documents page. Short proposals must be submitted via the electronic submission system of the Horizon 2020 Participant Portal.

Targeted immune intervention to treat non-response and relapse

The first topic of the Call addresses the needs of patients suffering from immune-mediated diseases who fail to respond to current standard-of-care treatments or undergo a rapid relapse. The goal is to identify new methods able to predict how patients will respond to treatment, in order to identify potential novel patient-centric treatment approaches.
Novel immunological biomarkers are expected to be identified to predict clinical responses; activities might include the analysis and profiling of immune cells obtained from non-blood tissues, the discovery of new, individual disease and cross-disease predictive biomarkers for disease, non-response, relapse and flare-up. These can be validated by mean of early phase clinical trials (e.g. enriched study populations for certain molecular pathways; adaptive and basket trial designs etc.), with a special focus on well-characterised immune-mediated diseases, such as lupus erythematosus, rheumatoid arthritis, ulcerative colitis, Chron’s disease, asthma and chronic obstructive pulmonary disease (COPD).
The translational precision-immunology research platform that should represent the main outcome of the Call should provide a more specific tool to improve patient management and help identify personalised treatment. The more accurate definition of subcategories of auto-immune disorders and their responses to particular therapies on the individual patient level are expected helping in the reduction of failure rates in early clinical trials; they will also support discovery of novel therapeutics and access to the most appropriate patient populations. Results might be also used in future to design platform trials for single indications with multiple mechanisms. Another expected target is the decrease of phase 2 proof of concept (POC) attrition and of the costs of development to be sustained by pharmaceutical companies to achieve regulatory approval and reimbursement.

Non-invasive clinical molecular imaging of immune cells

The second topic will parallel and support the goals of the first one though the establishment of a consortium to develop and validate a quantitative, non-invasive, immune cell imaging platform that should include novel and target-specific molecular imaging agents, (hybrid) imaging modalities, and image processing algorithms. The availability of non-invasive diagnostic methodologies is important to improve the penetration of precision medicine through the identification and stratification of patients and the prediction of therapeutic outcomes. Early diagnosis of the disease and/or its classification based on the immune phenotype should be also facilitated.
The topic aims to overcome the limits typical of current pharmacodynamic (PD) assessments of immune cells based on peripheral blood biomarkers or biopsy samples acquired by invasive procedures. Furthermore, already available imaging technologies provide limited information on time-dependent and disease-specific relevant immune cell subpopulations and compartments types, or measures of direct engagement of immune targets.
Immunotracers able to bind specific immune cells or targets within immune-mediated pathways would represent a definite advantage to address immune cell subtypes and immune markers of disease in a clinical setting, providing in vivo insights and improving knowledge about the pathophysiology of various immune-mediated diseases. The methodologies developed under this topic could provide an early indicator of whether patients are likely to benefit from a given (immuno-)therapeutic intervention (surrogate of response), also at the level of tissue/organ sites that are not biopsy-accessible. Another expected outcome of this action is related to a greater regulatory acceptance of standardised protocols using validated immune-imaging approaches, an important element that might significantly reduce the time and cost of clinical trials.

A platform for federated machine learning

Artificial intelligence and machine learning algorithms are rapidly emerging to play a central role in the development of new therapeutic interventions based on the acquisition and analysis of large amounts of big data. Large quantities of data are also generated during drug discovery activities, and their analysis has to be refined order to meet the complexity typical of biological systems. The third topic of the Call addresses this need, in order to optimise research activities, decrease development costs and improve regulatory acceptance of the generated data.
The new federated and privacy-preserving machine learning platform that is expected to be developed under the topic shall be initially validated on publicly accessible data in order to demonstrate the ability to preserve from illegitimate use of data. The technology is also expected to be scalable enough to be deployed to a significant representation of private data in the actual preclinical data warehouses of the participating major pharmaceutical companies in yearly evaluation runs.
In silico generated predictions obtained from the platform are expected to replace in future years pre-clinical in vitro testing and compound synthesis. A possible extension of this target might involve the application of similar concepts to clinical data, to enable faster recruitment of more targeted patients populations and real-world evidence analysis. The results of this action are also expected to improve access to data by third parties, “providing data owners with the confidence that their data and the corresponding predictive models will remain private”. Furthermore, federated learning represents a line of research and product development beyond that of data federation and specifically addressed to knowledge and Information and communication partners.

A Centre of Excellence for remote decentralised clinical trials

The last topic of the Call is focused on the creation of a new Centre of Excellence for the management of remote decentralised clinical trials. This action addresses the need to facilitate patients’ recruitment and retention in order to improve the adherence to clinical trial protocol. “Geography and the distance to the clinical site” has been identified by the 2017-global CISCRP survey as a burden for the 60% of patients, representing one of the reasons for a negative decision upon the participation to a clinical trial.
The topic aims to improve patients’ experience by disaggregating the current model of running clinical studies, while mapping new technologies (e.g. telemedicine, mobile health, etc.) that might support the new decentralised model. The projects should be focus on the demonstration of the feasibility of such model, reaching an higher speed of recruitment and a better retention. The follow-up phase of the trial should be also considered, to provide increased flexibility to patients and reducing the burden both on patients and hospitals. Among other targets of this topic is also the support to the update of the ICH guidelines all along the process by generating evidence.

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