Refocusing regulatory exclusivities: Regulatory data protection and marketing exclusivity as forms of pharmaceutical innovation policy

Protection of innovation in the pharmaceutical industry has traditionally been realised through protection of inventions via patents. However, in the European Union regulatory exclusivities restricting market entry of generic products confer tailored, industry specific protection for final, marketable products. This paper retraces the protection conferred by the different forms of exclusivity and assesses them in the light of recent transparency policies of the European Medicines Agency. The purpose of the paper is to argue for rethinking the role of regulatory data as a key tool of innovation policy and for refocusing the attention from patents to the existing regulatory framework. After detailed assessment of the exclusivity regime, the paper identifies key areas of improvement calling for reassessment so as to promote better functioning of the regime as an incentive for accelerated innovation. While economic and public health analysis necessarily provide final answers as to necessity of reform, this paper provides a legal perspective to the issue, appraising the current regulatory framework and identifying areas for further analysis.

Regulatory Mechanisms involved in Th2 Cell Differentiation. A Proteomics Approach.

Th2-solujen erilaistumista ohjaavat säätelyverkostot ja niiden tutkiminen proteomiikan avulla Astma ja allergiat ovat laajalle levinneitä ja vakavia sairauksia, joista kärsivät miljoonat ihmiset ympäri maailmaa. Koe-eläimillä tehdyt tutkimukset osoittavat, että interleukiini-4 (IL-4) on tärkeä allergisen astman ja allergioiden kehittymiselle ja kroonistumiselle. Se ohjaa T-auttajasolujen (Th-solujen) kehittymistä Th2-tyypin soluiksi, joilla on merkittävä rooli näiden tautien puhkeamisessa. Th2-solut tuottavat myös itse IL-4:ä, joka edesauttaa taudin seuraavien vaiheiden kehittymistä. Erityisesti STAT6-proteiini, joka aktivoituu IL-4-stimulaation seurauksena, on tarpeen Th2- vasteen syntymiselle ja kroonistumiselle antigeenin aiheuttamassa keuhkoputkien astmaattisessa tulehduksessa. Väitöskirjatyöni tarkoituksena oli käyttää kaksidimensionaaliseen elektroforeesiin (2- DE) perustuvaa proteomiikkaa ja massaspektrometriaa uusien Th2-solujen erilaistumista säätelevien proteiinien tunnistamiseksi. Erilaistumattomat Th-solut eristettiin vastasyntyneen napaverestä tai hiiren pernasta. Solut aktivoitiin Tsolureseptorin ja ns. ko-stimulatoristen reseptorien kautta ja erilaistettiin joko Th1- tai Th2-suuntaan vastaavasti erilaistavien IL-12- ja IL-4-sytokiinien avulla. Ensimmäisessä tutkimuksessa in vitro -erilaistettujen Th1- ja Th2-solujen proteomeja verrattiin keskenään proteiinien ilmenemisessä tai proteiinimodifikaatioissa olevien erojen tunnistamiseksi. Kaksi muuta päätutkimusta keskittyivät IL-4:n aiheuttamaan proteiinitason säätelyyn ensimmäisen vuorokauden aikana T-soluaktivaation jälkeen. Näistä ensimmäisessä IL-4:n aiheuttamia eroja tunnistettiin aktivoiduista ihmisen Thsoluista. IL-4:n todettiin säätelevän useita proteiineja kaspaasien välittämissä signalointiteissä sekä lisäävän T-solujen elävyyttä ja aktivoitumista. Toisessa tutkimuksessa STAT6-poistogeenisten hiirien lymfosyyttien proteomia verrattiin villityypin kontrollisoluihin T-soluaktivaation ja IL-4-stimulaation jälkeen. Näissä tutkimuksissa karakterisoitiin useita uusia IL-4:n ja STAT6:n kohdeproteiineja ja löydettiin uusia säätelyverkostoja. Tutkimustulokset ovat johtaneet uusiin Th2-erilaistumismekanismeja koskeviin hypoteeseihin.

Managing regulatory risks when outsourcing network-related services in the electricity distribution sector

Deregulation of the electricity sector liberated the electricity sale and production for competitive forces while in the network business, electricity transmission and distribution, natural monopoly positions were recognised. Deregulation was accompanied by efficiencyoriented thinking on the whole electricity supply industry. For electricity distribution this meant a transition from a public service towards profit-driven business guided by economic regulation. Regulation is the primary means to enforce societal and other goals in the regulated monopoly sector. The design of economic regulation is concerned with two main attributes; end-customer price and quality of electricity distribution services. Regulation limits the costs of the regulated company but also defines the desired quality of monopoly services. The characteristics of the regulatory framework and the incentives it provides are therefore decisive for the electricity distribution sector. Regulation is not a static factor; changes in the regulatory practices cause discontinuity points, which in turn generate risks. A variety of social and environmental concerns together with technological advancements have emphasised the relevance of quality regulation, which is expected to lead to the large-scale replacement of overhead lines with underground cables. The electricity network construction activity is therefore currently witnessing revolutionary changes in its competitive landscape. In a business characterised by high statutory involvement and a high level of sunk costs, recognising and understanding the regulatory risks becomes a key success factor. As a response, electricity distribution companies have turned into outsourcing to attain efficiency and quality goals. This doctoral thesis addresses the impacts of regulatory risks on electricity network construction, which is a commonly outsourced activity in the electricity distribution network sector. The chosen research approach is characterised as an action analytical research on account of the fact that regulatory risks are greatly dependent on the individual nature of the regulatory regime applied in the electricity distribution sector. The main contribution of this doctoral thesis is to develop a concept for recognising and managing the business risks stemming from economic regulation. The degree of outsourcing in the sector is expected to increase in years to come. The results of the research provide new knowledge to manage the regulatory risks when outsourcing services.

Genetic regulatory networks in avian B cells

Biology is turning into an information science. The science of systems biology seeks to understand the genetic networks that govern organism development and functions. In this study the chicken was used as a model organism in the study of B cell regulatory factors. These studies open new avenues for plasma cell research by connecting the down regulation of the B cell gene expression program directly to the initiation of plasma cell differentiation. The unique advantages of the DT40 avian B cell model system, specifically its high homologous recombination rate, were utilized to study gene regulation in Pax5 knock out cell lines and to gain new insights into the B cell to plasma cell transitions that underlie the secretion of antibodies as part of the adaptive immune response. The Pax5 transcription factor is central to the commitment, development and maintenance of the B cell phenotype. Mice lacking the Pax5 gene have an arrest in development at the pro-B lymphocyte stage while DT40 cells have been derived from cells at a more mature stage of development. The DT40 Pax5-/- cells exhibited gene expression similarities with primary chicken plasma cells. The expression of the plasma cell transcription factors Blimp-1 and XBP-1 were significantly upregulated while the expression of the germinal centre factor BCL6 was diminished in Pax5-/- cells, and this alteration was normalized by Pax5 re-introduction. The Pax5-deficient cells further manifested substantially elevated secretion of IgM into the supernatant, another characteristic of plasma cells. These results for the first time indicated that the downregulation of the Pax5 gene in B cells promotes plasma cell differentiation. Cross-species meta-analysis of chicken and mouse Pax5 gene knockout studies uncovers genes and pathways whose regulatory relationship to Pax5 has remained unchanged for over 300 million years. Restriction of the hematopoietic stem cell fate to produce T, B and NK cell lineages is dependent on the Ikaros and its molecular partners, the closely related Helios and Aiolos. Ikaros family members are zinc finger proteins which act as transcriptional repressors while helping to activate lymphoid genes. Helios in mice is expressed from the hematopoietic stem cell level onwards, although later in development its expression seems to predominate in the T cell lineage. This study establishes the emergence and sequence of the chicken Ikaros family members. Helios expression in the bursa of Fabricius, germinal centres and B cell lines suggested a role for Helios in the avian B-cell lineage, too. Phylogenetic studies of the Ikaros family connect the expansion of the Ikaros family, and thus possibly the emergence of the adaptive immune system, with the second round of genome duplications originally proposed by Ohno. Paralogs that have arisen as a result of genome-wide duplications are sometimes termed ohnologs – Ikaros family proteins appear to fit that definition. This study highlighted the opportunities afforded by the genome sequencing efforts and somatic cell reverse genetics approaches using the DT40 cell line. The DT40 cell line and the avian model system promise to remain a fruitful model for mechanistic insight in the post-genomic era as well.

Islet antigen-specific T cells and regulatory T cells in type 1 diabetes

T cells are the key players in the development of type 1 diabetes (T1D), mediating autoimmune reactions leading to the destruction of insulin producing beta cells in the islets. We aimed to analyze the role of different T-cell subtypes in the autoimmunity and pathogenesis of T1D. The frequency of islet antigen-specific (GAD65-, proinsulin-, and insulin-specific) CD4+ T cells was investigated in vitro in T1D patients, at-risk individuals (diabetes-associated autoantibody positive), and in controls, using MHC class II tetramers. An overall higher frequency of CD4+ T-cells recognizing the GAD65 555−567 peptide was detected in at-risk individuals. In addition, increased CD4+ T-cell responses to the same GAD65 epitope displaying a memory phenotype were observed in at-risk and diabetic children, which demonstrate a previous encounter with the antigen in vivo. Avidity and phenotypic differences were also observed among CD4+ T-cell clones induced by distinct doses of GAD65 autoantigen. T-cell clones generated at the lowest peptide dose displayed the highest avidity and expressed more frequently the TCR Vβ5.1 chain than low-avidity T cells. These findings raise attention to the antigen dose when investigating the diversity of antigen-specific T cells. Furthermore, an increased regulatory response during the preclinical phase of T1D was also found in genetically at-risk children. Higher frequencies of regulatory T (Treg) cells (CD4+CD25_high HLA-DR-/CD69-) and natural killer T (NKT) cells (CD161+Vbeta11+) were observed in children with multiple autoantibodies compared to autoantibody-negative controls. Taken together, these data showed increased frequency of islet-specific CD4+ T-cells, especially to the GAD65 555-567 epitope, and Treg and NKT cell upregulation in children at-risk for T1D, suggesting their importance in T1D pathogenesis

Role and regulatory mechanisms of heat shock factor 2

Protein homeostasis is essential for cells to prosper and survive. Various forms of stress, such as elevated temperatures, oxidative stress, heavy metals or bacterial infections cause protein damage, which might lead to improper folding and formation of toxic protein aggregates. Protein aggregation is associated with serious pathological conditions such as Alzheimer’s and Huntington’s disease. The heat shock response is a defense mechanism that protects the cell against protein-damaging stress. Its ancient origin and high conservation among eukaryotes suggest that the response is crucial for survival. The main regulator of the heat shock response is the transcription factor heat shock factor 1 (HSF1), which induces transcription of genes encoding protective molecular chaperones. In vertebrates, a family of four HSFs exists (HSF1-4), with versatile functions not only in coping with acute stress, but also in development, longevity and cancer. Thus, knowledge of the HSFs will aid in our understanding on how cells survive suboptimal circumstances, but will also provide insights into normal physiological processes as well as diseaseassociated conditions. In this study, the function and regulation of HSF2 have been investigated. Earlier gene inactivation experiments in mice have revealed roles for HSF2 in development, particularly in corticogenesis and spermatogenesis. Here, we demonstrate that HSF2 holds a role also in the heat shock response and influences stress-induced expression of heat shock proteins. Intriguingly, DNA-binding activity of HSF2 upon stress was dependent on the presence of intact HSF1, suggesting functional interplay between HSF1 and HSF2. The underlying mechanism for this phenomenon could be configuration of heterotrimers between the two factors, a possibility that was experimentally verified. By changing the levels of HSF2, the expression of HSF1-HSF2 heterotrimer target genes was altered, implementing HSF2 as a modulator of HSF-mediated transcription. The results further indicate that HSF2 activity is dependent on its concentration, which led us to ask the question of how accurate HSF2 levels are achieved. Using mouse spermatogenesis as a model system, HSF2 was found to be under direct control of miR-18, a miRNA belonging to the miR-17~92 cluster/Oncomir-1 and whose physiological function had remained unclear. Investigations on spermatogenesis are severely hampered by the lack of cell systems that would mimic the complex differentiation processes that constitute male germ cell development. Therefore, to verify that HSF2 is regulated by miR-18 in spermatogenesis, a novel method named T-GIST (Transfection of Germ cells in Intact Seminiferous Tubules) was developed. Employing this method, the functional consequences of miR-18-mediated regulation in vivo were demonstrated; inhibition of miR- 18 led to increased expression of HSF2 and altered the expression of HSF2 target genes Ssty2 and Speer4a. Consequently, the results link miR-18 to HSF2-mediated processes such as germ cell maturation and quality control and provide miR-18 with a physiological role in gene expression during spermatogenesis.Taken together, this study presents compelling evidence that HSF2 is a transcriptional regulator in the heat shock response and establishes the concept of physical interplay between HSF2 and HSF1 and functional consequences thereof. This is also the first study describing miRNA-mediated regulation of an HSF.

Metsäsääntely Suomessa ja Venäjällä. Näkökulmia kestävään metsätalouteen

Sustainability is the aim of forest management and forest regulation in many countries. Accordingly, forest management has been steered towards more environmentally friendly methods and new regulatory instruments have been introduced. At the same time, wood trade and forest industry have become a global business. Even if the importance of national forest legislation has not decreased, it has been widely acknowledged that national regulation of forest management is no longer sufficient. The movement of goods does not acknowledge boundaries, even though most negative environmental and social consequences stay in the country of origin of wood and other raw materials. As a partial solution to this dilemma, different kinds of regulations have been developed. Various forest certification schemes and wood trade regulation in the EU (995/2010) are examples of efforts to prevent illegal logging and unsustainable forestry. The Finland-based forest industry is to a varying extent dependent on wood trade from Russia. Especially in the 1990‟s, ethical questions concerning import of wood from Russian old growth forests near the Finnish border were widely discussed. Consequently, forest industry enterprises have developed systems to trace the origin of wood and to buy certified wood from Russia. The aim of the research has been to evaluate Finnish and Russian forest regulations in order to investigate what kind of forest management these regulations enhance, and to what extent ecologically sustainable forest management has been integrated into different forms of regulation. I have examined Finnish and Russian forest regulation in four separate articles based on the topics of the Russian Forest Code, forest certification and other voluntary forest protection measures in Russia, Finnish forest certification and Finnish forest legislation. One objective has been to analyse the roles voluntary forest certification plays in promoting sustainable forest management in different countries. In my research, I have mainly concentrated on ecological sustainability and protection of biodiversity, although other aspects of sustainable forest management have been touched upon in different articles. In the following I shall conclude the findings of my research. When the current Russian Forest Code (2006) was being adopted, the main emphasis was not on ecological issues, but on reorganizing forest governance. The role of ecological requirements was even slightly diminished during the legislative reform. There are, nevertheless, still stipulations aiming at ecological sustainability, such as the division of forests into different forest management categories and various protection zones. In 2000, FSC forest certification arrived in Russia, at present covering already 28 million hectares of forests. The PEFC scheme is now in use as well, but to a much lesser extent. If properly implemented, Russian forest certification schemes clearly improve the level of ecological and social sustainability of forestry in Russia. Certification criteria, however, are partly in conflict with the Russian forest legislation and certified enterprises have been forced to pay fines or to negotiate with forest authorities. This clearly indicates that even if Russian forest legislation has otherwise been liberalized to a certain extent, some significant paternalism still exists. Voluntary, hands-on biodiversity protection measures are not valued, and they are not part of the official protection policies as in many other countries. However, there have been some regional solutions to this dilemma. In the Republic of Karelia forest authorities have approved a set of forest biodiversity protection rules created by a local NGO and a forest industry enterprise. By following these local rules, an enterprise can avoid fines for protection measures. The current Finnish Forest Act was adopted in 1996. It brought forest legislation into a new era as some ecological aspects were integrated into forest legislation. The various soft-law forest management recommendations further increased the level of biodiversity protection. My evaluation of the overall legitimacy of the Finnish forest legislation and forest management paradigm revealed, however, several problematic issues. As part of this study I analysed the history of the current forest management paradigm. This analysis revealed the path dependency which still hinders the protection of biodiversity and clearly decreases the general legitimacy of forest management. Due to several historical reasons only even-structured forest management based on clear cuts has for decades been officially approved in Finland. Due to increasing demands of forest owners the legislation is finally being revised. Yet, the official approval of uneven-structured forest management would not be enough to fully improve ecological, social and cultural legitimacy. The latest ecological theories and knowledge of endangered species should be taken into account in the on-going reform of forest legislation as well as the modernisation. Forest legislation is one of the very few spheres of Finnish environmental legislation where openness and participation are still considered a threat. The first Finnish forest certification scheme, PEFC, was established in 2000. It now covers more than 20 million hectares, about 95% of the forests in Finland. PEFC Finland does not require a higher level of biodiversity protection than the recommendations by Tapio (the Development Centre for Forestry), but certification has unified forest management practices and requires more protection measures than mere forest legislation. The study suggests that in Finland PEFC has not functioned as an instrument which would substantially improve the level of forest management. Rather it has supported the status quo of the forest sector. While the ecological and social responsibility of Finland-based forest corporations was one impetus for this research, I want to conclude that there are problems related to forest legislation and non-state regulation in both Finland and Russia. If an enterprise buying wood from Russia buys only certified wood, and carefully avoids wood coming from high conservation value forests that are either ecologically or socially valuable, it can be claimed to be as sustainably produced as in Finland. However, there must be continuous scrutiny of the circumstances. In Russia, the level of the compliance of certification criteria varies considerably, and there are vast unprotected invaluable forest areas. The utilisation of these areas should not be based on short-sighted decisions or lack of consensus among stakeholders.

Biomarkers - regulatory and toxicological perspectives

Referaatti kongressiesitelmästä.

Licensing Model Development for Small Modular Reactors (SMRs) - Focusing on the Finnish Regulatory Framework

Recently, Small Modular Reactors (SMRs) have attracted increased public discussion. While large nuclear power plant new build projects are facing challenges, the focus of attention is turning to small modular reactors. One particular project challenge arises in the area of nuclear licensing, which plays a significant role in new build projects affecting their quality as well as costs and schedules. This dissertation - positioned in the field of nuclear engineering but also with a significant section in the field of systems engineering - examines the nuclear licensing processes and their suitability for the characteristics of SMRs. The study investigates the licensing processes in selected countries, as well as other safety critical industry fields. Viewing the licensing processes and their separate licensing steps in terms of SMRs, the study adopts two different analysis theories for review and comparison. The primary data consists of a literature review, semi-structured interviews, and questionnaire responses concerning licensing processes and practices. The result of the study is a recommendation for a new, optimized licensing process for SMRs. The most important SMR-specific feature, in terms of licensing, is the modularity of the design. Here the modularity indicates multi-module SMR designs, which creates new challenges in the licensing process. As this study focuses on Finland, the main features of the new licensing process are adapted to the current Finnish licensing process, aiming to achieve the main benefits with minimal modifications to the current process. The application of the new licensing process is developed using Systems Engineering, Requirements Management, and Project Management practices and tools. Nuclear licensing includes a large amount of data and documentation which needs to be managed in a suitable manner throughout the new build project and then during the whole life cycle of the nuclear power plant. To enable a smooth licensing process and therefore ensure the success of the new build nuclear power plant project, management processes and practices play a significant role. This study contributes to the theoretical understanding of how licensing processes are structured and how they are put into action in practice. The findings clarify the suitability of different licensing processes and their selected licensing steps for SMR licensing. The results combine the most suitable licensing steps into a new licensing process for SMRs. The results are also extended to the concept of licensing management practices and tools.

Maritime safety in the Gulf of Finland. Evaluation of the regulatory system

Growing traffic is believed to increase the risk of an accident in the Gulf of Finland. As the consequences of a large oil accident would be devastating in the vulnerable sea area, accident prevention is performed at the international, regional and national levels. Activities of shipping companies are governed with maritime safety policy instruments, which can be categorised into regulatory, economic and information instruments. The maritime regulatory system has been criticised for being inefficient because it has not been able to eliminate the violations that enable accidents. This report aims to discover how maritime governance systems or maritime safety policy instruments could be made more efficient in the future, in order to improve the maritime safety level. The results of the research are based on a literature review and nine expert interviews, with participants from shipping companies, interest groups and authorities. Based on the literature and the interviews, a suggestion can be made that in the future, instead of implementing new policy instruments, maritime safety risks should be eliminated by making the existing system more efficient and by influencing shipping companies’ safety culture and seafarers’ safety related attitudes. Based on this research, it can be stated that the development of maritime safety policy instruments should concentrate on harmonisation, automation and increasing national and cross-border cooperation. These three tasks could be primarily accomplished by developing the existing technology. Human error plays a role in a significant number of maritime accidents. Because of this, improving companies’ safety culture and voluntary activities that go beyond laws are acknowledged as potential ways of improving maritime safety. In the future, maritime regulatory system should be developed into a direction where the private sector has better possibilities to take part in decision-making.

Non-profit maximising organisations and the impact of privatisation, liberalisation, and public-sector reform

I denna avhandling analyserar jag både offentliga och privata företag och organisationer, inklusive universitet, särskilt när det existerar potentiell inre motivation. Jag behandlar både industriell produktion, inklusive infrastruktursektorer med vertikala relationer, och tjänstesektorn. Man tänker sig att ägandet kan påverka kostnadseffektiviteten dels genom olika storlek hos lönetillägg och andra förmåner för de anställda (eng. Internal Rent Capture), och dels via asymmetrisk information. Jag frågar dessutom om det finns andra faktorer än ägande och konkurrens som kan påverka prestandan hos kommersiella företag och ideella organisationer. Dessa frågeställningar aktualiseras av pågående reformer inom den offentliga sektorn, särskilt i samband med den så kallade nya offentliga förvaltningen (eng. New Public Management). Jag analyserar reformernas inverkan på hur bra en organisation fungerar och på den sociala välfärden. Analysen i denna avhandling är teoretisk, men resultaten är relaterade också till den empiriska litteraturen. Avhandlingen är uppdelad i del I och II. I del I sammanfattar jag avhandlingen och sätter den i ett sammanhang, medan del II består av fem redan publicerade essäer. De två första (I–II) är mera traditionella, i och med att de baserar sig på homo economicus (eng. the economic man), utan att beakta den inre motivationen. I essä I (publicerad 2008) bedömer vi fördelar och nackdelar av privatisering och avreglering innanför en sådan ram, men med en betoning också på icke återvinningsbara fasta kostnader och vertikala relationer. I essä II (publicerad 2012) fokuserar vi oss på vertikal separation, och konkurrensutsättning och privatisering i nätverksindustrier. I essäerna III–V vidgas perspektivet genom att införa potentiell inre motivation i en agentmodell. Analysen i essä III (publicerad 2014) tillämpas på offentligt ägande och privatisering. I essäerna IV och V (publicerade 2009 respektive 2013) utvidgas analysen till att även gälla kreativa branscher, särskilt arbete inom universiteten, där den inre motivationen hos de anställda kan tänkas vara avgörande. I dessa essäer tillämpas en analys som inbegriper ett intra-personellt spel inom ramen för en agentmodell med potentiell inre motivation. Vi analyserar sålunda avvägningen mellan ekonomiska incitament och inre motivation.