The objective of this research is to develop and apply a HILIC UHPLC stationary phase that allows for separation of intact glycoproteins. In Chapter 1 I give an overview of the problems of current glycosylation profiling with regards to biotherapeutics, and my strategy to separate the intact glycoprotein with HILIC. Chapter 2 describes the methods used to produce the nonporous packing material and stationary phase. In Chapter 3 I describe previous work in developing a HILIC polyacrylamide stationary phase, and further improvements I have made. Chapter 4 describes development of an assay in collaboration with Genentech of therapeutic mAb glycosylation. In Chapter 5, I show HILIC-MS of digested ribonuclease B as a beginning step to analyze glycosylated biomarkers.

隨著人口增長以及人口老化速度加劇，全球藥品消費需求快速成長。生物藥品因其具有針對特定疾病之專一性，在治療病毒性肝炎、癌症及後天免疫缺乏症候群（Acquired Immunodeficiency Syndrome，AIDS）等重大疾病上擁有相當大的發展潛力。除了積極研發全新生物藥品之外，我國生技製藥廠商亦將注意力放到生物相似性藥品的研發上。 但因我國藥品內需市場規模較小，一旦成功研發出生物相似性藥品，若無法將其外銷至海外市場，恐不能弭平鉅額的前期投入。而進入國際市場之際，倘若未制定適宜的進入策略，卻又極可能會以失敗收場。 基於生物相似性藥品本身之特性與法律上之定義，其研發藥廠在進入市場的順序上係處於後進者之地位。但為了成為早期追隨者而搶占部分先驅者優勢，廠商必須選擇恰當的進入模式及進入時機並適時的調整之。而進入障礙對於進入策略之擬定有相當大的影響，尤其以生物相似性藥品市場而言，影響最為深刻的是制度性的進入障礙。 本研究以全球前二大藥品市場─美國、中國大陸為標的，探討我國生物相似性藥品研發廠商進入海外生物相似性藥品市場時，所需跨越的制度性進入障礙可能為何？其他跨國性藥廠在面臨上述制度性進入障礙時，係採取何種因應方法，以及如何調整其進入策略？並從中總結出，對於我國生物相似性藥品研發廠商而言，較為可行的市場進入策略。 經研究分析後，本研究認為，生物相似性藥品市場的制度性進入障礙係來自於東道國的保護主義、專利相關法規與解決專利爭議之機制有所缺漏或偏頗，以及藥品上市審查及藥價管理相關法律規範過於嚴苛或過於鬆散。 而跨國性藥廠因有較充裕的資金及專利訴訟經驗，因此在面對因專利所形成之制度性進入障礙時，可以訴訟或法定行政程序等合法方式克服該專利障礙。對於藥品上市審查法規之要求，則可透過加大投資以求符合法規標準。至於東道國的保護主義，則多藉由與當地企業進行合作、成立合資企業等方式，突破該進入障礙。 因我國生物相似性藥品研發廠商之規模較小，較難獨自克服各生物相似性藥品市場的制度性進入障礙，所以在進入策略上，本研究建議，可積極尋求與原廠或國際生物相似性藥品研發廠商合作，致力於發展全新生物藥品。或是透過兩岸合作研發，於奠定一定基礎後，進一步開拓生物相似性藥品的海外市場。

Advances in molecular immunology and rapid technical evolution during the past two decades have led to a new class of medicines called biologics. Recently, a large number of biologics, or biologic immunomodulators, directed towards an array of immune–mediated diseases, have entered the market. This has lead to a dramatic change in the immunotherapy of autoimmune diseases, as biologics present new potential to improve or substitute conventional immunosuppressive therapies. According to literature, biologics are used by only a small number of a health plan’s members, (approximately one per cent), but a single occurrence can be relatively expensive. Furthermore, there is an indication that the frequency of use and cost of biologics are on the rise, and as more biologics enter the market, health plans and employers face the challenge of controlling costs while ensuring that biologics are affordable. The general objective of this study was to determine the prevalence and cost of biologic immunomodulating medicine in the treatment of certain autoimmune diseases during the period 2005 to 2008 in a section of the private health care sector of South Africa, by employing a medicine claims database as a source to obtain necessary information. A quantitative, retrospective drug utilisation review (rDUR) was performed on computerised medication records (medicine claims data) for four consecutive years (i.e. 2005 to 2008) provided by a pharmacy benefit management company (PBM). The study population consisted of all patients on the database who received at least one medicine item with adalimumab, etanercept, infliximab, interferon beta–1a, interferon 1–b or rituximab as active ingredient and who were diagnosed with either rheumatoid arthritis (RA), multiple sclerosis (MS) or Crohn’s disease between 1 January 2005 and 31 December 2008. Between 2005 and 2008, an average of 1,305,201 patients appeared on the total database, and of these 0.055% (n = 713) received biologic immunomodulating medicine. More than two thirds of biological users were female and most patients who received these medicine items were between the ages of 39 and 64 years, followed by those patients aged between 25 and 39 years. Biologic immunomodulating medicine items (n = 11,914) and biologic prescriptions (n = 9,537) represented 0.016% of the total number of medicine items (N = 76,129,173) and 0.030% of the total number of prescriptions (N = 31,985,153). The percentage contribution of biologic immunomodulators to the total number of medicine items and prescriptions on the total database increased each year, and in four years’ time the percentage of all the medicine items on the total database that included biologic immunomodulators had tripled, from 0.009% to 0.023%. The total cost of biologic immunomodulating medicine accounted for 1.278% of the total cost (N = R7, 483,759,176.23) of all medication claimed through the PBM between 2005 and 2008. The percentage contribution of biologic immunomodulators to the total medicine expenditure also increased from one year to another for the four–year study period. The average cost of a biologic immunomodulating medicine item increased with 71.10% from 2005 (R5602.71 ± 2166.61) to (R9586.25 ± 5956.56) in 2008. The CPI for biologic immunomodulators, (CPI = 60.00 for 2005; CPI = 74.62.17 for 2006; CPI = 85.26 for 2007; and CPI = 86.96 for 2008) indicated that biologic immunomodulating medicine items were relatively expensive and the d–value between the average cost per biologic immunomodulator and the average cost per non–biological medicine item (d–value = 2.54 in 2005, d–value = 3.32 in 2006, d–value = 2.23 in 2007 and d–value = 1.59 in 2008) furthermore indicated that the impact of biological therapies was large and practically significant. Rheumatoid arthritis patients represented 19.78% of the total number of patients (n = 713) who claimed the biologic immunomodulators during the four–year period, MS patients (n = 172) represented 24.12% and Crohn’s patients (n = 11) represented 1.5%. Biological drugs prescribed to RA patients represented 0.28% (n = R20, 708,818.82) of the total cost (N = R7, 483,759,176.23) of all medication claimed through the PBM during the four–year period, while those prescribed to MS patients represented 0.41% (R30, 922,520.07) and those prescribed to Crohn’s disease patients represented 0.015% (R1, 108,568.02). Although biologic immunomodulating medicine items used in the treatment of RA, MS and Crohn’s disease are relatively expensive, it seems that the number of other medication prescribed to patients with these diseases decreased after treatment with biologics, which may influence the medicine treatment cost of these patients. It can be concluded that even though biologic immunomodulators are used by only a very small percentage of the total patient population in a section of the private health care sector of South Africa, they are relatively expensive and have a considerable impact not only the medical aid scheme, but also on the patient. / Thesis (M.Pharm (Pharmacy Practice))--North-West University, Potchefstroom Campus, 2011.

Advances in molecular immunology and rapid technical evolution during the past two decades have led to a new class of medicines called biologics. Recently, a large number of biologics, or biologic immunomodulators, directed towards an array of immune–mediated diseases, have entered the market. This has lead to a dramatic change in the immunotherapy of autoimmune diseases, as biologics present new potential to improve or substitute conventional immunosuppressive therapies. According to literature, biologics are used by only a small number of a health plan’s members, (approximately one per cent), but a single occurrence can be relatively expensive. Furthermore, there is an indication that the frequency of use and cost of biologics are on the rise, and as more biologics enter the market, health plans and employers face the challenge of controlling costs while ensuring that biologics are affordable. The general objective of this study was to determine the prevalence and cost of biologic immunomodulating medicine in the treatment of certain autoimmune diseases during the period 2005 to 2008 in a section of the private health care sector of South Africa, by employing a medicine claims database as a source to obtain necessary information. A quantitative, retrospective drug utilisation review (rDUR) was performed on computerised medication records (medicine claims data) for four consecutive years (i.e. 2005 to 2008) provided by a pharmacy benefit management company (PBM). The study population consisted of all patients on the database who received at least one medicine item with adalimumab, etanercept, infliximab, interferon beta–1a, interferon 1–b or rituximab as active ingredient and who were diagnosed with either rheumatoid arthritis (RA), multiple sclerosis (MS) or Crohn’s disease between 1 January 2005 and 31 December 2008. Between 2005 and 2008, an average of 1,305,201 patients appeared on the total database, and of these 0.055% (n = 713) received biologic immunomodulating medicine. More than two thirds of biological users were female and most patients who received these medicine items were between the ages of 39 and 64 years, followed by those patients aged between 25 and 39 years. Biologic immunomodulating medicine items (n = 11,914) and biologic prescriptions (n = 9,537) represented 0.016% of the total number of medicine items (N = 76,129,173) and 0.030% of the total number of prescriptions (N = 31,985,153). The percentage contribution of biologic immunomodulators to the total number of medicine items and prescriptions on the total database increased each year, and in four years’ time the percentage of all the medicine items on the total database that included biologic immunomodulators had tripled, from 0.009% to 0.023%. The total cost of biologic immunomodulating medicine accounted for 1.278% of the total cost (N = R7, 483,759,176.23) of all medication claimed through the PBM between 2005 and 2008. The percentage contribution of biologic immunomodulators to the total medicine expenditure also increased from one year to another for the four–year study period. The average cost of a biologic immunomodulating medicine item increased with 71.10% from 2005 (R5602.71 ± 2166.61) to (R9586.25 ± 5956.56) in 2008. The CPI for biologic immunomodulators, (CPI = 60.00 for 2005; CPI = 74.62.17 for 2006; CPI = 85.26 for 2007; and CPI = 86.96 for 2008) indicated that biologic immunomodulating medicine items were relatively expensive and the d–value between the average cost per biologic immunomodulator and the average cost per non–biological medicine item (d–value = 2.54 in 2005, d–value = 3.32 in 2006, d–value = 2.23 in 2007 and d–value = 1.59 in 2008) furthermore indicated that the impact of biological therapies was large and practically significant. Rheumatoid arthritis patients represented 19.78% of the total number of patients (n = 713) who claimed the biologic immunomodulators during the four–year period, MS patients (n = 172) represented 24.12% and Crohn’s patients (n = 11) represented 1.5%. Biological drugs prescribed to RA patients represented 0.28% (n = R20, 708,818.82) of the total cost (N = R7, 483,759,176.23) of all medication claimed through the PBM during the four–year period, while those prescribed to MS patients represented 0.41% (R30, 922,520.07) and those prescribed to Crohn’s disease patients represented 0.015% (R1, 108,568.02). Although biologic immunomodulating medicine items used in the treatment of RA, MS and Crohn’s disease are relatively expensive, it seems that the number of other medication prescribed to patients with these diseases decreased after treatment with biologics, which may influence the medicine treatment cost of these patients. It can be concluded that even though biologic immunomodulators are used by only a very small percentage of the total patient population in a section of the private health care sector of South Africa, they are relatively expensive and have a considerable impact not only the medical aid scheme, but also on the patient. / Thesis (M.Pharm (Pharmacy Practice))--North-West University, Potchefstroom Campus, 2011.

Užití biologických materiálů k náhradě tkání v plastické chirurgii ! Abstrakt v angličtině Background: Biological meshes are biomaterials consisted of extracellular matrix and used in surgery particularly for hernia treatment or thoracic wall reconstruction. They are capable of vascularization, that decreases risk of infection, expecially when used in contaminated fields. This study compared the strength of incorporation and biocompatibility of two porcine-derived grafts (cross-linked and non-cross-linked) in a rat hernia model. In addition, we hypothesized that combination of extracellular matrices with autologous mesenchymal stem cells used for hernia repair would result in increased vascularization and increased strength of incorporation. Methods: Standardized 2 x 4 cm fascial defect was created in 42 Wistar rats and repaired with a cross-linked or a non-cross-linked graft either enriched or non-enriched with stem cells. The rats were sacrificed 3, 6 and 12 months later. The strength of incorporation, vascularization, cellular invasion, foreign body reaction and capsule formation were evaluated. Results: Comparison of stem cell enriched and non-enriched groups showed no significant differences in the capsule thickness, foreign body reaction, cellularization or vascularization. In the non-cross-linked...

Užití biologických materiálů k náhradě tkání v plastické chirurgii ! Abstrakt v angličtině Background: Biological meshes are biomaterials consisted of extracellular matrix and used in surgery particularly for hernia treatment or thoracic wall reconstruction. They are capable of vascularization, that decreases risk of infection, expecially when used in contaminated fields. This study compared the strength of incorporation and biocompatibility of two porcine-derived grafts (cross-linked and non-cross-linked) in a rat hernia model. In addition, we hypothesized that combination of extracellular matrices with autologous mesenchymal stem cells used for hernia repair would result in increased vascularization and increased strength of incorporation. Methods: Standardized 2 x 4 cm fascial defect was created in 42 Wistar rats and repaired with a cross-linked or a non-cross-linked graft either enriched or non-enriched with stem cells. The rats were sacrificed 3, 6 and 12 months later. The strength of incorporation, vascularization, cellular invasion, foreign body reaction and capsule formation were evaluated. Results: Comparison of stem cell enriched and non-enriched groups showed no significant differences in the capsule thickness, foreign body reaction, cellularization or vascularization. In the non-cross-linked...

BPCIA在2010年三月生效後，生物相似藥廠商開始可以利用簡化的文件向美國食品和藥物管理局（FDA）申請藥品許可證，這個新醫療法賦予FDA決定如何落實法案的權力。基於不同生物製劑之間缺乏比較性這個已知的事實，加上公眾安全的考量，在還沒有累積大量經驗可以歸納出哪些是比較分析必要的資訊之前，FDA會保守的要求生物相似藥廠商以BPCIA提出申請時，必須提供臨床試驗資料來證明與參照藥品之間沒有臨床上有意義的差異。 雖然BPCIA給出了解決專利糾紛的框架，俗稱專利舞蹈(patent dance)，依照目前聯邦巡迴上訴法院對BPCIA的解釋，認為BPCIA法案不強制生物相似藥申請者遵循其規定之專利糾紛解決程序，雖然就目前的最新發展來看，迴避專利舞蹈可以避免一些程序上的麻煩，但真正參照藥品廠商和生物相似藥公司的輸贏仍是在訴訟戰場上見真章。 美國FDA在2015年3月6日核准了的一個生物相似藥-Zarxio( filgrastim-sndz)，目前尚不清楚均等論這種不確定性在生物相似藥上影響的程度，但藉由簡化新藥申請上市的小分子藥物所涉入的侵權訴訟做有限度的推論可以發現，小分子藥物的均等謬論案件是牽涉到外圍專利，當專利不再提供足夠的誘因去激勵專利權人時，學名藥廠商就會贏得均等論謬論案件。因為生物製劑是一種製程決定的產物，因此其專利通常是集中在製程。以BPCIA和專利法為框架來分析過去的相關侵權訴訟，可以預測生物相似藥廠商在轉化前步驟、轉化步驟、調劑、或包裝做改變，其成功的機會較大，而在細胞培養會純化步驟做改變，成功的機會最小。然而，最終還是要看法院將來如何解決生物相似藥的侵權問題，各方都要意識到科學與法律議題的複雜性，及妥適解決侵權訴訟的重要性。 台灣廠商要進入生物相似藥的領域，是困難重重的。生物相似藥的開發及法規成本，不如想像中低，鑒於蛋白質藥『產能』一直被看作是市場發展受阻的主要原因，藥廠委外合作(CRO、CMO或NRDO) 的模式能快速與國際藥廠接軌，逐步奠定台灣在藥物開發的供應鏈合作利基並提昇國際知名度。 / The Biologics Price Competition and Innovation of 2009 was activated on March in 2010. Now the US Food and Drug Administration (FDA) can approve biosimilars and was empowered to how to practice. Given the known issues with lack of comparability between different biologics preparations, and the Agency’s strong interest in protecting public safety, it is probable that, until it has developed a body of experience with regards to the amount and kind of data needed to make comparability evaluations, the FDA will adopt a conservative approach and require at least some clinical studies before approving biologics under BPCIA. Though BPCIA provide the frame for resolving patent issues, that is so-called patent dance, Federal Circuit said that parties were not compelled to dance. Thus the law uncertainty was shifted to patent infringement. FDA approved the first biosimilar, Zarxio (filgrastim-sndz), on 6, March, 2015. It is unclear how biosimilar will be treated in court based on doctrine of equivalence. Based on the experience from generics, courts tends to adjust the scope of equivalents to improve the correspondence between patent scope and desired patent incentives. In contrast, biologics is path depended. That is to say process decided what biologics would be. Both the BPCIA and patent law guide the shape of infringement suits. Follow-on biologics companies will be most successful when they make a change in the pretransformation process, the transformation process, the formulation, or the packaging. They will be least successful when they make a change in the cell culture conditions or the purification process. It remains to be seen how courts will address issues of infringement for follow-on biologics, but all parties should be aware of the complexity of the scientific and legal issues and the importance of addressing them properly. The cost for development and the complexity of regulation in biosimilars were tremendously high. Thus it is difficult for biopharmaceutical industries in Taiwan to enter this field. In the light of unmet production capacity in protein drug, pharmaceutical industries in Taiwan could apply the mode of CRO, CMO or NRDO to integrate into global biopharmaceutical community.

生物藥品是很多先前具致命性和難以治療的疾病領域，像是癌症、自體免疫疾病及神經系統疾病內最被看好的現行新穎療法。近年來，隨著探索出突破性小分子藥物愈趨困難，加上生物藥品在新藥研發過程中有較低的折損率與較高的成功產出率，使得越來越多藥廠紛紛轉向開發利潤豐厚的大分子生物產品。此外許多暢銷生物藥品專利期即將屆至，從而帶來對相對價廉、通常被稱為原廠生物藥品仿製版本之「生物相似性藥品」的龐大治療需求。然而，由於生物藥品和小分子藥物在分子大小及結構複雜程度方面存在截然不同的特性與本質差異，因此建立一套專屬於生物相似性藥品的上市許可規範勢在必行。 作為於2010年3月23日正式簽署公告之「患者保護及可負擔照護法案」中的一部分，美國國會通過了「生物藥品價格競爭與創新法」(BPCIA)。BPCIA的生效被視為製藥產業最重要的變革之一，旨在藉由競爭達到維護公眾健康、促進生物技術創新和控制醫療支出之目的，同時取得適當之三方利益平衡。BPCIA即以Hatch-Waxman法案下的化學學名藥核准途徑為模版，創建生物藥品簡易上市申請程序。 本論文的結構主要區分為兩大部分進行研究，其一提供了製藥產業概觀與全球生物藥品市場的發展趨勢，其二則聚焦在BPCIA新建立的核准前專利爭端解決程序下，生物相似性藥品面臨「專利舞蹈」時的法律評估及智慧財產權管理。 論文的第一部分係根據從各種市場研究報告收集、整理而成的統計數據，以系統性的方式深入介紹全球製藥產業，並分析生物相似性藥品的市場機會和潛在隱憂。另外此部分亦詳細說明了生物相似性藥品的生理活性、知識斷層與製程依賴性之間的關係、分析技術對生物產品做完整定性的不足以及生物相似性藥品的開發流程。 論文的第二部分則以討論BPCIA的重要條文規定為主，包括專利舞蹈制度和上市審查要求，諸如生物相似性之證明、可互換性之認定與適應症外推。其他相關議題，包含參考藥品的法定專屬權保護期長度、生物相似性藥品自動替換之立法化、專利資訊交換機制的可能濫用及原廠與生物相似藥廠達成反競爭協議之風險皆會予以進一步探討。除此之外，本部分也介紹了歐盟和台灣生物相似性藥品上市法規的沿革與現況。 本文試圖透過對生物相似性藥品的全方位綜合研究成果，提出可行的市場進入方案及善用專利和營業祕密優勢之智慧財產權保護佈局策略。 / Biologics represent many of the most promising novel therapies for previously deadly and intractable disease areas like cancer, autoimmune disease and neurological disorders. As discovery of breakthrough small-molecule drugs becomes more difficult, together with lower attrition rate and higher productivity of biologics in the new drug research and development (R＆D) process, pharmaceutical companies are increasingly turning to develop lucrative large-molecule biological products in recent years. In addition, the patents on numerous blockbuster biologics treatments will soon expire, bringing soaring demand for relatively inexpensive generic versions of originator biologics, generally known as “biosimilars.” However, due to contrasting characteristics and natural differences in terms of size and structural complexity between biologics and small-molecule drugs, it is necessary to create a regulatory pathway solely for biosimilars. As part of the Patient Protection and Affordable Care Act which was officially signed into law on March 23, 2010, the U.S. Congress passed the Biologics Price Competition and Innovation Act (BPCIA). The BPCIA is considered one of the more significant overhauls to the pharmaceutical industry, aiming to strike a proper balance among securing public interests, stimulating biotechnology innovation and controlling healthcare expenditure through competition. It established an abbreviated approval pathway for biosimilars modeled closely after the Hatch-Waxman Act’s approval process for generic chemical drugs. The structure of this thesis is divided into two major parts, of which the first part provides an overview of pharmaceutical industry and trends in the global biologics market, whereas the second part focuses on the legal assessment and intellectual property management of biosimilars under BPCIA’s new pre-approval patent dispute resolution process, the “patent dance”. The first part starts from the in-depth systematic introduction of global pharmaceutical industry based on statistics collected from various market research reports, then analyzes the market opportunities and potential concerns for biosimilars. Moreover, this part illustrates the physiological properties, the relationship between “knowledge gap”and manufacturing path-dependence, the insufficieny of analytical techniques in fully characterizing biological products, and the development process of biosimilars in details. The second part discusses key provisions of the BPCIA, including the patent dance procedures and regulatory requirements, such as demonstrating biosimilarity, interchangeability and extrapolation. Other relevant issues include the length of statutory exclusivities granted to reference products, legislations on biosimilar automatic substitution, potential abuses of patent information exchange mechanism and risks of reaching anti-competitive agreements between pioneers and biosimilar manufacturers will be further discussed. Besides, this part describes the timeline and status quo of EU and Taiwan’s biosimilar approval regulations. With comprehensive study on multiple aspects of biosimilars, this article tries to propose feasible market access plans and robust intellectual property protection strategies capitalizing upon patents and trade secrets.

Le génie tissulaire est un domaine interdisciplinaire qui applique les principes du génie et des sciences de la vie (notamment la science des cellules souches) dans le but de régénérer et réparer les tissus et organes lésés. En d'autres mots, plutôt que de remplacer les tissus et les organes, on les répare. La recherche en génie tissulaire est considérable et les ambitions sont grandes, notamment celle de mettre fm aux listes d'attente de dons d'organes. Le génie tissulaire a déjà commencé à livrer des produits thérapeutiques pour des applications simples, notamment la peau et le cartilage. Les questions sur la façon de réglementer les produits thérapeutiques qui sont issus du génie tissulaire sont soulevées à chaque nouveau produit. À ce jour, ces questions ont reçu peu d'attention comparativement aux questions éthiques associées aux recherches avec les cellules souches et les risques qu'engendrent les produits biologiques. Il est donc important d'examiner si le cadre normatif qui entoure la mise en marché des produits issus du génie tissulaire est approprié puisque de tels produits sont déjà disponibles sur le marché et plusieurs autres sont en voie de l'être. Notre analyse révèle que le cadre canadien actuel n'est pas approprié et le moment d'une reforme est arrivé. Les États-Unis et l'Union européenne ont chacun des approches particulières qui sont instructives. Nous avons entrepris une revue des textes réglementaires qui encadrent la mise en marché des produits issus du génie tissulaire au Canada, aux États-Unis et dans l'Union européenne et formulons quelques suggestions de réforme. / Tissue engineering is an interdisciplinary field that applies the principles of engineering and the life sciences (including the science of stem cells) toward the development of biological substitutes that restore, maintain or improve tissue function. In other words, rather than being replaced, tissues and organs are repaired. Research in tissue engineering is important and ambitions are high, such as ending the waiting list for organ transplant. Tissue engineering has already started delivering therapeutic products for simple applications such as skin and cartilage. Questions on the way tissue engineered therapeutic products are regulated are raised with each new product. Until now, these questions have been given little attention compared to the ethical issues related to stem cell research and to the risks generated by biologics. It is therefore important to examine whether the regulatory framework is suitable since some tissue engineered products are already available on the market and others are soon to be marketed. Our analysis reveals that the Canadian regulatory framework is not suitable and the time is ripe for reform. The United States and the European Union have their own approaches that are instructive. We have undertaken a study of the regulatory premarket approval frameworks in Canada, United States and the European Union, and formulated suggestions for reform.

Le génie tissulaire est un domaine interdisciplinaire qui applique les principes du génie et des sciences de la vie (notamment la science des cellules souches) dans le but de régénérer et réparer les tissus et organes lésés. En d'autres mots, plutôt que de remplacer les tissus et les organes, on les répare. La recherche en génie tissulaire est considérable et les ambitions sont grandes, notamment celle de mettre fm aux listes d'attente de dons d'organes. Le génie tissulaire a déjà commencé à livrer des produits thérapeutiques pour des applications simples, notamment la peau et le cartilage. Les questions sur la façon de réglementer les produits thérapeutiques qui sont issus du génie tissulaire sont soulevées à chaque nouveau produit. À ce jour, ces questions ont reçu peu d'attention comparativement aux questions éthiques associées aux recherches avec les cellules souches et les risques qu'engendrent les produits biologiques. Il est donc important d'examiner si le cadre normatif qui entoure la mise en marché des produits issus du génie tissulaire est approprié puisque de tels produits sont déjà disponibles sur le marché et plusieurs autres sont en voie de l'être. Notre analyse révèle que le cadre canadien actuel n'est pas approprié et le moment d'une reforme est arrivé. Les États-Unis et l'Union européenne ont chacun des approches particulières qui sont instructives. Nous avons entrepris une revue des textes réglementaires qui encadrent la mise en marché des produits issus du génie tissulaire au Canada, aux États-Unis et dans l'Union européenne et formulons quelques suggestions de réforme. / Tissue engineering is an interdisciplinary field that applies the principles of engineering and the life sciences (including the science of stem cells) toward the development of biological substitutes that restore, maintain or improve tissue function. In other words, rather than being replaced, tissues and organs are repaired. Research in tissue engineering is important and ambitions are high, such as ending the waiting list for organ transplant. Tissue engineering has already started delivering therapeutic products for simple applications such as skin and cartilage. Questions on the way tissue engineered therapeutic products are regulated are raised with each new product. Until now, these questions have been given little attention compared to the ethical issues related to stem cell research and to the risks generated by biologics. It is therefore important to examine whether the regulatory framework is suitable since some tissue engineered products are already available on the market and others are soon to be marketed. Our analysis reveals that the Canadian regulatory framework is not suitable and the time is ripe for reform. The United States and the European Union have their own approaches that are instructive. We have undertaken a study of the regulatory premarket approval frameworks in Canada, United States and the European Union, and formulated suggestions for reform.