The impact of religion on human embryonic stem cell regulations: comparison between the UK, Germany and the US

Author byline as per print journal: Hajaj M Alhomaidan; Ali M Alhomaidan, PhD

Abstract:
This paper describes the differences in human embryonic stem cell regulations in several Christian countries across the world: Italy, Spain, the UK, Germany and the US. It discusses issues related to Catholic and Protestant countries and how the differences in religious ideologies do not seem to be reflected in stem cell regulations. For example, in the UK, Germany and the US, that have largely Protestant ideologies, the stem cell regulations differ dramatically, with Germany being the most stringent globally and the UK’s the most permissive. It concludes by noting that predominantly Protestant Christian countries have different human embryonic stem cell regulations to one another and that this does not seem to be in line with their religious backgrounds.

Submitted: 5 October 2017; Revised: 1 January 2018; Accepted: 11 January 2018; Published online first: 24 January 2018

Introduction

A country’s regulations can influence the innovation of industries, companies and entire economies. Yet, the impact of regulations in the empirical literature is judged with ambivalence when it comes to innovation [1]. Different regulations generate different results and even a single type of regulation can affect innovation in diverse ways depending on how the regulation is interpreted [1].

In this paper, several Christian countries with different embryonic stem cell regulations are examined. The countries in which the Roman Catholic denomination is largest are Austria, Canada, France, Italy, The Netherlands, Spain and Switzerland. The predominantly Protestant countries examined in this paper are Australia, Denmark, Finland, Germany, Sweden, the UK and the US. The percentages of predominant religious denominations in these countries are shown in Tables 1 and 2.

Table 1

One would be inclined to assume that countries with the same religious background should have similar embryonic stem cell regulations. Predominantly, Protestant countries might be expected to be permissive of embryonic stem cell research while predominantly Roman Catholic countries should be restrictive. This, however, is not true. To illustrate this, the predominantly Roman Catholic countries of Italy and Spain are compared, as are the predominantly Protestant countries of the UK, Germany and the US.

Embryonic stem cell regulations in Christian countries

Italy’s citizenry is predominantly Roman Catholic and embryonic stem cell research regulations are restrictive [2, 4]. One could argue that this is due to lobbying by the Roman Catholic Church and to the fact that 90% of Italians follow its teachings. On the other hand, Spain’s public is also predominantly Roman Catholic, with 94% of the public following the church’s teachings [2]. However, embryonic stem cell research is carried out in Spain using leftover embryos from in vitro fertilization (IVF) [5]. In addition, Spain legalized therapeutic cloning becoming the fourth country in Europe to do so [5]. In 2004, Spain also created Europe’s third stem cell bank and established three research centres exclusively studying regenerative medicine and stem cells [5]. Based on that, one cannot generalize that if a country’s public is predominantly Roman Catholic, the country’s regulations would be opposed to human embryonic stem cell research.

The same is true for Protestant countries. However, it cannot be argued that if a country were predominantly Protestant it would have permissive regulations regarding this controversial form of research. Not all Protestants approve of human embryonic stem cell research. And conservative Protestants and mainline Protestants have different views regarding such research. Official positions on the moral status of the embryo vary from country to country and, therefore, so do positions on the morality of embryo research in general. For instance, the UK is a predominantly Protestant country known for its permissive human embryonic stem cell regulations. However, Germany is also a predominantly Protestant country, but it is restrictive to human embryonic stem cell research [6].

The Evangelical Protestant Church of Germany is also divided on the topic of stem cells [6]. These divisions demonstrate how personal the views on embryonic stem cell research can be. For the public and the aforementioned churches, weighing up the need to help suffering people and the moral status of the embryo is not a simple issue. Therefore, from the observed differences between the predominantly Roman Catholic and the predominantly Protestant, it is not possible to establish a relationship between the predominant religion in a given country and embryonic stem cell regulations that can be generalized to other countries not included in this thesis.

Why do countriess such as the UK, Germany and the US, which all have a strong Protestant background, have different embryonic stem cells regulations?

It can be a difficult ethical and scientific balance for policies to reflect the importance of retaining the shared moral views of a nation, along with the desire to advance in disease management. Human embryonic stem cell research is a topic still fraught with dispute, both between and within nations. Protestants are also divided on ethics of embryonic stem cell research. The discrepancy in policies throughout the world demonstrates the ethical criticisms of stem cell research coupled with their therapeutic potential. The following will provide a historical background regarding the UK, Germany, and the US, and the events that led to the establishment of such different restrictive or permissive regulations in countries with similar Protestant backgrounds [7].

The UK
The UK is a predominantly Protestant Christian country with permissive human embryonic stem cell regulations. These regulations can be traced back to a 1982 committee that was known as the Committee of Inquiry into Human Fertilisation and Embryology, also known as the Warnock Committee. The committee was headed by Helen Warnock, a British philosopher of education, mind and morality. This committee was established to make recommendations regarding potential and recent developments in science and medicine related to human fertilization and embryology [8]. The recent developments referred to the birth of Louise Brown, the world’s first ‘test-tube baby’, who was born in England in 1978 [8]. One aim of the committee was to consider what safeguards and policies should be put in place, including reflection of the moral, social and legal implications of these developments [8]. In 1985, the Report of the Committee of Inquiry into Human Fertilisation and Embryology (Warnock Report) was made public by the committee in the UK.

The committee recommended that research on human embryos only be performed for clear purposes that are considered necessary and desirable. In addition, such research can only be performed on an embryo 14-days-old or younger [8]. Not all members of the committee agreed on these recommendations. Three took the view that life begins at conception and did not agree with these recommendations [8]. In addition, other bioethicists outside the committee did not agree with all the recommendations. For example, John Harris, a philosopher, argued that the 14-day limit on embryo research was arbitrary and too short [9]. On the other hand, Harris also said that the 14-day limit has been valuable. He said that ‘by pure luck, huge amounts have been learned: it does turn out that most of the things we needed to do in terms of stem cell research can be done before the 14-day limit [10]’.

In 1990, The Report of the Committee of Inquiry into Human Fertilization and Embryology gave rise to the Human Fertilisation and Embryology Act and the Human Fertilisation and Embryology Authority (HFEA). This authority regulates human fertility experimentation and treatment using human embryos This means that they regulate the licensing for procedures, such as in vitro fertilization (IVF) and they oversee the ban on research using human embryos older than 14 days [11]. In 2002, the HFEA issued the first license for human embryonic stem cell research in the UK, using surplus embryos from IVF [11]. These events shaped the UK embryonic stem cell regulations in place today. Now, the UK has permissive embryonic stem cell regulations and it is considered one of the world’s pioneers in reproductive and regenerative medicine. The UK allows the production of embryonic stem cell lines from leftover IVF embryos. Furthermore, the cloning of embryos to generate stem cell lines for therapeutic purposes is only legally allowed in the UK [12].

Germany
Much like the UK, Germany is predominantly a Protestant country. However, unlike the UK, Germany has one of the strictest embryonic stem cell policies seen worldwide [13]. In 1990, the Embryo Protection Act was passed by the German Parliament. This act gave the German Government control over the therapeutic measures used in reproductive medicine to overcome human infertility. One of the goals of this act was to prevent unwanted commercial uses of human embryos [13]. As far as reproductive medicine is concerned, the Embryo Protection Act constitutes the world’s most restrictive law for embryonic research. The act outlaws any research on human cleavage stages or blastocysts not clearly designed to safeguard the embryo’s survival [14]. Embryo research can now be carried out only as long as a clinical pregnancy remains possible and the embryo is not harmed during or following the study. The Embryo Protection Act contains the following punishable stem cell research related acts:

Anyone who acquires, disposes of, or uses for a purpose not serving its safeguarding, a human embryo produced outside the body, or removed from a woman before the conclusion of implantation in the uterus, will be imprisoned for up to three years or receive a fine [14].
Similarly, anyone who causes a human embryo to develop further outside the body for any purpose other than pregnancy will be punished [14].

The Director of Education at the National Catholic Bioethics Center, Dr Tadeusz Pacholczyk, on the topic of embryonic stem cell research noted, ‘Germany, which has a strong historical memory of the consequences of ignoring human dignity, declines to participate in these charades [7]’. Reverend Pacholczyk was referring to the history of unethical medical experimentation conducted by the Nazi regime throughout World War II. Germany now strongly regulates IVF treatments and only allows the production of no more than three embryos for each IVF procedure; all three embryos must be implanted into the womb [15]. Germany outlaws genetic testing of embryos, cloning of embryos, experimentation on embryos, and the production of extra embryos [15].

Even though the Embryo Protection Act makes the use and production of human embryos for research purposes a punishable offense, it does not clearly make illegal the importation of human embryonic stem cells from other countries. In 2002, the German Parliament exploited this loophole and established the Stem Cell Act. This act allows the import of human embryonic stem cells for research purposes in Germany [13]. To ensure that no human embryonic stem cells lines are directly produced for German research purposes, only human embryonic stem cell lines produced from surplus embryos from IVF prior to the 1 January 2002 can be lawfully imported [13]. In 2008, the ban on creating human embryonic stem cell lines in Germany was upheld by the national parliament of the Federal Republic of Germany. However, the cutoff date was changed from 1 January 2002 to 1 May 2007 [16]. Here it is important to point out that there is a German ethical double standard in this law and it is illogical to allow an act that is banned on German embryos to be carried out on embryos imported from other countries.

The US
Unlike Germany, in the US, research with human embryonic stem cells is not forbidden, but scientists can only use cell lines produced from surplus IVF embryos created prior to 9 August 2001 if the research is financed with federal money [4]. Privately funded research on human embryonic stem cell or the production of human embryonic stem cell lines is not regulated by federal law [4]. Human embryonic stem cell research is nationally inconsistent in the US. Several states such as California, Massachusetts and New Jersey have passed legislation that can be described as permissive. Other states such as Arkansas, Iowa, Kansas, Louisiana, North Dakota, South Dakota and Virginia have banned human embryonic stem cell research [4].

The restrictions on embryonic research can be traced back to 1977. In that year, the Federal Policy for the Protection of Human Subjects was enacted. It stated that ‘No application or proposal involving human in vitro fertilization may be funded by the Department or any component thereof until the application or proposal has been reviewed by the Ethical Advisory Board and the Board has rendered advice as to its acceptability from an ethical standpoint [17]’.

In 1993, former President Bill Clinton instigated the National Institutes of Health Revitalization Act, which abolished the Federal Policy for the Protection of Human Subjects [13]. This paved the way for federal backing of grant applications to research human fertilization with no need for supplementary examination by an Ethical Advisory Board. However, President Clinton received thousands of letters urging him to overturn his previous decision. He agreed, and federal funding of embryonic research was suspended 1994 [13].

In 1995, through the Dickey-Wicker Amendment, Congress banned federal funding for research on embryos. This amendment forbids the use of federal funds for the production of human embryos for research purposes; or research in which human embryos are discarded, destroyed, or consciously subjected to risk of damage or death larger than that tolerated for research on fetuses in utero [13]. In 2006, Congress passed a bill that would relax restrictions on federal funding for human embryonic stem cell research. The bill was known as the Stem Cell Research Enhancement Act. However, then-President George W Bush vetoed this bill, citing his religious beliefs as grounds for his decision [18]. Thus, restrictions on research continued throughout the Bush presidency.

In March, 2009, President Barack Obama reversed Bush’s executive order, removing barriers to federal funding of scientific research involving human embryonic stem cells [19]. However, in August 2010, an injunction blocking President Obama’s Executive Order was issued by Federal District Court Judge Royce Lamberth [20]. Judge Lamberth argued that Obama’s Executive Order goes against the Dickey-Wicker Amendment [20]. The court’s decision is the result of a lawsuit filed in August 2009 against the National Institutes of Health (NIH) and the Department of Health and Human Services (HHS) in Maryland. Dr James Sherley, one of the plaintiffs in the case argued that federal funding for research on human embryonic stem cells is unlawful since the destruction of embryos is necessary [21]. The plaintiffs contended that the new policy infringed the Dickey-Wicker Amendment. In response, the Obama Administration’s lawyers argued that the new policy would fund human embryonic stem cells research after the stem cells are already extracted from the embryos [21] and that no funding is to be given to the actual destruction of the embryos. Therefore, the Obama Administration contended that the NIH guidelines do not violate the Dickey-Wicker Amendment. In September 2010, The US Court of Appeals for the D.C. Circuit lifted Judge Lamberth’s injunction that stopped funding throughout the lawsuit [22]. In July 2011, Judge Lamberth dismissed the case. He said that ‘the NIH reasonably interpreted an executive order by President Obama directing it to remove some restrictions on the support of stem-cell research [22]’. These circumstances demonstrate the uncertain nature of the legal standing of human embryonic stem cell research in the US. These events that were initiated by President Clinton and continued through the Bush and Obama presidencies show that human embryonic stem cell research regulations are ambiguous in the US and that these regulations are influenced by both politics and religion. Legislation should be put in place to remove this uncertainty.

Conclusion

One would be inclined to assume that countries with the same religious background should have similar embryonic stem cell regulations. However, this paper showed that predominantly Protestant Christian countries have different human embryonic stem cell regulations to one another. Several Christian countries with different regulations were examined including Italy, Spain, the UK, Germany and the US. The UK has permissive embryonic stem cells regulations. In Spain, regulations are moderate whilst in Italy, Germany and the US they are restrictive.

Competing interests: The author has no affiliations with or involvement in any organization or entity with any financial or non-financial interest in the subject matter discussed in this paper.

Provenance and peer review: Not commissioned; externally peer reviewed.

Authors

Hajaj M Alhomaidan, MBBS Senior Student
Street No. 60, House No. 9B, Alyasmin District, Riyadh 13322, Saudi Arabia

Ali M Alhomaidan, PhD
Executive Director for Products Evaluation
Saudi Food and Drug Authority, 3292 North Ring Road – Al Nafal Unit (1), Riyadh 13312-6288, Saudi Arabia

References
1. Information Technology & Innovation Foundation. Stewart LA. The impact of regulation on innovation in the United States 2010: a cross-industry literature review [homepage on the Internet]. [cited 2018 Jan 1]. Available from: https://www.itif.org/files/2011-impact-regulation innovation.pdf.
2. Central Intelligence Agency. The World Factbook [homepage on the Internet]. [cited 2018 Jan 1]. Available from: https://www.cia.gov/library/publications/the-world-factbook/
3. Frost & Sullivan. U.S Stem cell market: current developments. 2008.
4. Knowles LP. The use of human embryos in stem cell research. 2009.
5. Cervera RP, Stojkovic M. Developments and challenges in human embryonic stem cell research in Spain. Stem Cell Rev. 2009;5(4):334-9.
6. Tuffs A. Germany eases ban on embryonic stem-cell lines. Nature. 2008;452(7189):796.
7. Pacholczyk T. Human stockpiling. The Boston Pilot. 2011 Sep 9.
8. Department of Health & Social Security. Warnock M, Baker TSG, Barnes J, Carriline MM, Davies D, Dyson AO, Edwards NL, Greengross, et al. Report of the Committee of Inquiry into Human Fertilisation and Embryology. 1984 [homepage on the Internet]. [cited 2018 Jan 1]. Available from: http://www.bioeticacs.org/iceb/documentos/Warnock_Report_of_the_Committee_of_Inquiry_into_Human_Fertilisation_and_Embryology_1984.pdf
9. Harris J. The value of life: an introdution to medical ethics. Routledge. 1985. p. 112-17.
10. Harris J. Stem cells, sex, and procreation. Cambridge Quarterly of Healthcare Ethics. 2003;12(4):353-71.
11. Lefort R. Concern as Human Fertilisation and Embryology Authority figures show large rise in IVF mistakes. The Telegraph. 2010 Apr 25.
12. Callaway E. European court bans patents based on embryonic stem cells. Nature. 2011. doi:10.1038/news.2011.597
13. Gottweis H, Prainsack B. Emotion in political discourse: contrasting approaches to stem cell governance in the USA, UK, Israel and Germany. Regenerative Med. 2006;1(6):823-9.
14. Bundestag. The Embryo Protection Act. 1990. p. 2746.
15. Beier H, Beckman J. Implications and consequences of the German Embryo Protection Act. Human Reproduction. 1991:6(4):607-8.
16. Herrmann I, Woopen C, Brüstle O. German parliament passes amendment to Stem Cell Act. 2008.
17. U.S. Department of Health and Human Services. Research involving pregnant women or fetuses. In: 45CFR § 46204.
18. CNN. Bush vetoes embryonic stem-cell bill. 2006 Sep 25.
19. Stolberg S. Obama lifts Bush’s strict limits on stem cell research. New York Times. 2009 Mar 9.
20. Harris G. U.S. Judge rules against Obama’s stem cell policy. The New York Times. 2010 Aug 23.
21. Ertelt S. Scientists appeal to stop Obama’s embryonic stem cell funding. Bioethics. 2011 Sep 20.
22. Fischman J. U.S. judge dismisses lawsuit that threatened stem-cell research. The Chronicle of Higher Education. 2011 Jul 27.

Author for correspondence: Ali M Alhomaidan, PhD, Executive Director for Products Evaluation, Saudi Food and Drug Authority, 3292 North Ring Road – Al Nafal Unit (1), Riyadh, Saudi Arabia

Disclosure of Conflict of Interest Statement is available upon request.

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Pricing of biosimilars in Saudi Arabia

Author byline as per print journal: Ali M Alhomaidan, PhD; Ibrahim A Aljuffali, MSc, PhD; Fahad S Alnutaifi, MHEcon, MPH; Nasseruddeen A AL-Howaimel, MSc

Abstract:
Innovation in the pharmaceutical industry is expensive and risk must be rewarded. Some novel pharmaceuticals may be worth their high prices. Yet, high prices may hinder accessibility to novel products. It is paramount for pharmaceutical companies to demonstrate the value of their products in the face of increasingly budget-conscious stakeholders. This paper will provide background on the pricing of biosimilars in Saudi Arabia and explain the system used for pricing these products. Factors influencing pricing of pharmaceuticals in general as well as approaches to pharmaceuticals price control worldwide will be discussed.

Submitted: 7 January 2016; Revised: 17 March 2016; Accepted: 19 March 2016; Published online first: 31 March 2016

Introduction: pricing of pharmaceuticals

Pharmaceuticals are one of the vital products that are subject to regulatory control in Saudi Arabia. The reason for regulation is due to the fact that pharmaceuticals are one of the most important elements of many countries’ healthcare programme spending and one of the central factors contained in the citizen spending basket, especially for low-income families, which is reflected on the health of the population [1]. A system that installs pharmaceutical prices could be considered as an interference with the economic concept that says that the price of the commodity is determined by supply and demand [2]. It can also be seen as a hindrance to innovation [3]. However, it is not patients who decide what pharmaceutical they will use based on information available to them, whether it is for its properties, advantages, or price. Rather, patients depend on the physician or pharmacist to select the prescribed pharmaceutical based on several factors that direct their choice and affects their decision. Therefore, patients are at the mercy of their doctor or pharmacist [1]. Generally, prices are negotiated by governments to meet policy objectives and by pharmaceuticals manufacturers to attain profitability.

Factors influencing pricing of pharmaceuticals

Although it is easy to calculate the cost of manufacturing and marketing of a drug, it is difficult to calculate the total cost of getting a pharmaceutical product to the market. Therefore, the pharmaceutical companies price their products by allocating the cost distribution of all the elements involved in getting products to the market including research and development, production and quality control, administrative expenses, marketing, and distribution and retailing. However, by looking at pharmaceuticals prices and seeing differences in price between countries, one can argue that there are other factors influencing price than the total cost of manufacturing and selling these products. Examples of these factors include:

Income per capita [4]
Degree of state influence on drug pricing [4]
Market size [5]
Fluctuations in currency rates [5]
The cost of marketing and the possibility of it reaching consumers in the country. For instance, pharmaceutical companies cannot advertise directly to patients in Saudi Arabia, which affects demand
The existence of intellectual property protection system in the country [1].

Approaches to pharmaceuticals price control worldwide

Due to high prices of pharmaceuticals worldwide, which have led to increased economic pressure on countries, countries are trying to control prices through regulation and by encouraging commercial competition among pharmaceutical companies by making way for the marketing of generics and biosimilars. In the face of these developments, countries found themselves obliged to intervene to determine the prices of pharmaceuticals in order to adjust public spending on pharmaceuticals and encourage local pharmaceutical industry growth in a way that ensures the availability of effective and safe pharmaceuticals in their markets. Countries have historically controlled prices of pharmaceuticals through one of the following options:

Full Control in the price system. This is used in Saudi Arabia and several countries in the Middle East and North Africa (MENA) region. In Saudi Arabia, it is mostly applied in the pricing of new chemical entities or innovator products. In Saudi Arabia, the company submits pricing certificates showing the price of its product in the country of origin and its price in the countries where it is marketed (Form 30). A price is set based on ex-factory price. A maximum of 2% is then added for the cost, insurance and freight (CIF price) and 10–15% is added for wholesaler profit, with another 10–20% added for retail profit when it is sold to the public [6]. The percentage depends on ex-factory or CIF price; see Table 1. Despite the difficulties in the application of the system in terms of auditing of certificates and authentication, including outages, it has helped greatly in stabilizing prices in the country and preventing fluctuations. The pricing committee can review prices when there is a change in exchange rates that might affect the availability of products in the Saudi market. In the case of change of price in the country of origin, or in the case that the company asks for a change in price, an appeal against set price is allowed within 60 days of the decision with proper justification [6].
Ceiling price system. The regulator sets an upper limit on the price of the pharmaceutical to be marketed without committing the company to this price. The company is free to sell its products at any price based on market conditions and marketing policy as long as it is less than ceiling price. One of the main benefits of this system is that it opens the field to competition between companies and pharmacies and increases the sales of generic drug products [8]. The success of this system, however, requires an effective regulatory system and the presence of generic drugs industry with an accompanying advanced system and strict sanctions on companies, pharmacies and health practitioners who engage in the unethical marketing of products [8].
Open pricing system. Pricing is left to pharmaceutical companies and retail pharmacies to sell pharmaceuticals at a price that will bring them a reasonable profit without interference from a regulator, allowing market forces to determine the price. This system is applied in the US, and it is noted that the prices of pharmaceuticals in the US are one of the highest in the world [9].
Reference pricing. This is applied mostly to generic drug products in Saudi Arabia. Generics are priced based on the price given to innovator products or new chemical entities. The reference product’s price is reduced by 20% at the license of the first generic drug, which is priced 35% cheaper than the reference product before a reduction in the reference product price; every subsequent generic drug is 10% cheaper, until the fourth generic drug. The reduction in price then stops. For example, if a reference product is priced at Saudi Riyals 100, when the first generic is registered, the price will be reduced to Saudi Riyals 80, the first generic will be Saudi Riyals 65, and subsequent generics 10% cheaper, till the fourth generic. An appeal against set price in Saudi Arabia can be lodged within 60 days of the decision with proper justification.

Fig 1

Evolution of pharmaceuticals pricing in Saudi Arabia

In 1935, the law of pharmaceuticals use was issued by the Royal Decree No. 157/1/18 [10]. The law regulated the practice of pharmacy and the opening of retail pharmacies in Saudi Arabia. The system for pricing of pharmaceuticalswas first issued by Royal Decree No. 12 on 1953, which required the determination of pharmaceuticals prices and set a 15% profit for each of the wholesaler and retail pharmacies. Royal Decree No. M/37 on 1961 was then issued which raised the proportion of profits allowed for the sale of pharmaceuticals by retail pharmacies to 17% of the value of their purchase from the wholesaler. Profits specified for wholesalers remained the same without any increase or decrease of 15% of the value of the imported pharmaceuticals. Royal Decree No. M/37 also required wholesalers to put pricing stickers on every imported pharmaceutical [11].

This continued until 1977 when the Ministerial Decree No. 7 issued the regulations for the registration and pricing of pharmaceuticals [12]. Registration and pricing of pharmaceuticals were entrusted for the first time to the Registration Committee at the Ministry of Health. The committee was to use the following when estimating the price:

The price of pharmaceuticals to the public in the country of origin
The price of pharmaceuticals in other countries
The price is not to exceed export prices to Saudi Arabia for wholesale selling prices in the exporting country.

Regulations also required to provide a number of reference pricing certificates when filing for registration such as certificates describing the selling price to the public in the country certified by the source of the concerned governmental authorities and from the Saudi embassy there or its substitute [12].

In 2004, the law of pharmaceutical products and establishments was issued. It determined in article XIII the proportion of profit is calculated for retail and wholesalers according to Table 1. One of the objectives of this law was to encourage the marketing of cheaper pharmaceuticals with smaller packages by giving higher margins for products at Saudi Riyals 50 or cheaper [13]. In 2008, the responsibility for licensing and pricing of pharmaceuticals was transferred from the Ministry of Health to the Saudi Food and Drug Authority (SFDA). The pricing system was then reviewed by the Registration Committee. A draft executive regulation for the law for pharmaceutical establishments and products was issued and approved by SFDA’s Board of Directors in 2011 and is still in effect [14]. The new system included rules for the first time that allow for lowering innovative pharmaceuticals price by 20% when SFDA license its first generic pharmaceutical. The new system also encouraged the marketing of generic pharmaceuticals and the transfer of manufacturing to the Kingdom. It also gives permissions to the Registration Committee to take required measures to ensure the availability of pharmaceuticals in the Saudi market.

Pricing of biosimilars

A Full Control in the price system is applied to biosimilars in Saudi Arabia. Based on regulatory pricing requirements, the manufacturer is to provide a prices certificate certified by the competent authority in the country of origin and authenticated by the Saudi Embassy that contains information on the following:>

Ex-factory Price
Wholesaler Price, in the country of origin
Retail Price, a wholesale price plus expenses, and retail pharmacy profit, which is the final price paid by the patient
The proposed export price of the company’s product to the Kingdom
Form 30, which shows the price in 30 different countries, in case it is registered in these countries. Table 2 shows a list of these countries.

Fig 2

We will use Remsima, a biosimilar for Remicade (Infliximab), as an example. The company submitted pricing certificates showing the ex-factory price at Saudi Riyals 1,126.029. The cost of insurance and freight was added. Since the ex-factory price is more than Saudi Riyals 200, only 10% is added for the wholesaler profit, and another 10% is added for the retail profit when it is sold to the public. The final price is Saudi Riyals 1,362.50.

Conclusion

Factors influencing pricing of pharmaceuticals in general as well as approaches to pharmaceuticals price control worldwide were discussed in this paper. Pricing of biosimilars in Saudi Arabia and the system used for pricing these products was presented. Remsima was used as an example to illustrate the pricing system. Biosimilars are priced using the Full Control in the price system. Remsima was the first biosimilar registered in Saudi Arabia for Infliximab. The reference product, Remicade, is priced at Saudi Riyals 2,127.95 whilst Remsima is priced at Saudi Riyals 1,362.50, which is about 36% cheaper than Remicade. Applying this pricing system should reduce the price of biosimilars in Saudi Arabia when compared to innovator reference products, allowing for more patient accessibility and affordability. However, it may put pressure on biosimilars manufacturers due to the high costs associated with their development. Hopefully in the long term, this can be negated with more manufacturers entering this niche market. In addition, there is clarity now compared to a few years ago when the regulatory pathways worldwide were not clear regarding data requirements for biosimilars. Now the requirements are clear and some of these products are well characterized. Still, I think we will yet have a Hatch-Waxman moment for biosimilars where the regulatory requirements are streamlined allowing for more competition between manufacturers and for more investments. As it stands, biosimilars are still a high-risk investment.

Competing interests: The authors have no affiliations with or involvement in any organization or entity with any financial or non-financial interest in the subject matter discussed in this paper.

Provenance and peer review: Commissioned; externally peer reviewed.

Co-authors

Ibrahim A Aljuffali¹, MSc, PhD
Executive Vice President for Drug Affairs
Fahad S Alnutaifi¹, MSc
Nasseruddeen A AL-Howaimel¹, MSc

¹Saudi Food and Drug Authority

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9. International Federation of Health Plans. 2013 Comparative price report: variation in medical and hospital prices by country [homepage on the Internet]. [cited 2016 Mar 17]. Available from: http://www.ifhp.com/
10. Royal Decree number 157/1/18: The law of pharmaceuticals use 1935.
11. Royal Decree number 37/M. 1961.
12. Ministerial Decree No. 7: The regulations for the registration and pricing of pharmaceuticals. 1971.
13. Royal Decree number 31/M: The law for pharmaceutical establishments and products. 2004.
14. The Saudi Food and Drug Authority: Executive regulation for the law for pharmaceutical establishments and products 2011.

Author for correspondence: Ali M Alhomaidan, PhD, Executive Director for Products Evaluation, Saudi Food and Drug Authority, 3292 North Ring Road – Al Nafal Unit (1), Riyadh, Saudi Arabia

Disclosure of Conflict of Interest Statement is available upon request.

Source URL: https://gabi-journal.net/pricing-of-biosimilars-in-saudi-arabia.html

First GCC stakeholder meeting on approval process, interchangeability/substitution and safety of biosimilars 2017 – Report

Author byline as per print journal: Gianluca Trifirò, MD, PhD; Meteb Al-Foheidi, MD, FRCPC; Ali M Alhomaidan, PhD; Ahmed H Aljedai, PharmD, MBA, BCPS, FCCP, FAST; Musaed Abdullah Alkholief, PhD; Mohammad A Alsenaidy, MSc, PhD; Aws Alshamsan, BPharm, RPh, PhD; Tore Kristian Kvien, MD, PhD

Introduction: A meeting was organized by the Generics and Biosimilars Initiative (GaBI) in collaboration with Saudi Pharmaceutical Society (SPS), to discuss the regulation, approval process, interchangeability/substitution, and post-marketing surveillance of biosimilars in Gulf Cooperation Council (GCC) countries. This ‘First GCC Stakeholder Meeting on Approval Process, Interchangeability/Substitution and Safety of Biosimilars’, took place on 20 November 2017, in Riyadh, Saudi Arabia and gave relevant stakeholders an opportunity to discuss these concepts between themselves and with experts from Saudi Arabia and abroad.
Methods: The meeting brought regulators from GCC countries and academics, medical specialists, and pharmacologists and pharmacists from Saudi Arabia together with experts from Italy, Norway, Saudi Arabia and the US, to share knowledge and exchange information. There were a number of expert speaker presentations with an interactive panel discussion. Following this, the audience was presented with data for two semi-fictional similar biotherapeutic products. The participants were divided into two discussion groups where they evaluated the fictional data supplied.
Results: The presentations were successful in conveying information about the current state of biosimilar regulation, approval, interchangeability/substitution, and post-marketing surveillance of effectiveness and safety. This resulted in a useful interactive discussion from which clearly defined action points could be extracted.
Conclusion: Biosimilar medicines are becoming increasingly available and used across GCC countries. The First GCC biosimilars stakeholder meeting was successful in bringing representatives from GCC nations together with those from Europe and the US, to discuss the best routes forward for successful biosimilar approval and regulation and enabled action points to facilitate biosimilar uptake with appropriate pharmacovigilance to be outlined.

Submitted: 22 November 2018; Revised: 27 November 2018; Accepted: 28 November 2018; Published online first: 11 December 2018

Introduction

Appropriate methods for the approval and regulation of similar biotherapeutic products (SBPs or biosimilars) are subject to global discussion [1, 2]. To ensure that biosimilars successfully enter markets and maintain the safety and efficacy achieved by originator products, approval and regulation guidelines need to be clearly outlined. In addition, it is important to define interchangeability/substitution so that products are used in a way that does not impact on safety and efficacy.

To discuss the regulation and approval of biosimilars in the Gulf Cooperation Council (GCC) countries such as Bahrain, Kuwait, Oman and Saudi Arabia, the First GCC Stakeholder Meeting on Approval Process, Interchangeability/Substitution and Safety of Biosimilars, took place on 20 November 2017, in Riyadh, Saudi Arabia. It was organized by the Generics and Biosimilars Initiative (GaBI) in collaboration with Saudi Pharmaceutical Society (SPS). Fifty-four participants, speakers included, attended the meeting.

This first GCC biosimilars stakeholder meeting was an interactive scientific meeting on the regulation, approval and use of biosimilars with a focus on their interchangeability/substitution and safety. It brought regulators from GCC countries, and academics, medical specialists, and pharmacologists and pharmacists (clinical, hospital) from Saudi Arabia; together with experts from Italy, Norway and the US, to share knowledge and exchange information.

The meeting aimed to address the issues of physicochemical characterization, analytical comparability, interchangeability/substitution and safety of biologicals/biosimilars. The participants engaged in active discussion concerning regulatory approval process, cell line development, hospital formulary selection, switching, and set out to identify future educational needs.

Expert speaker presentations

The format of the GCC meeting was similar to that followed in previous educational workshops and scientific meetings as reported in the GaBI Journal [3–5]. There were a number of expert speaker presentations followed by Q&A and an in-depth panel discussion. The presentations are downloadable from the GaBI website [6].

The GCC meeting began with a welcome from Professor Yousif A Asiri, Vice Rector of Planning and Development and Professor of Clinical Pharmacy at King Saud University (KSU), Saudi Arabia. This was followed by an introduction by Abdulaziz Alhossan, Assistant Professor at KSU, and then a series of presentations given by expert speakers [6].

The false myths of biosimilars
Clinical Pharmacologist and Professor Gianluca Trifirò, of the University of Messina, Italy gave a presentation during which he discussed and dispelled various ‘false myths’ surrounding biosimilar products. These were outlined as follows:

– Biosimilars are not identical but only similar to the reference product, thus they should be considered as different drugs
– Pre-marketing evidence on biosimilars are much more limited than what is available for the reference product at the time the drug is marketed
– Biosimilars are less safe than reference product in routine care
– Interchangeability of biosimilars and reference product should never be considered due to serious immunogenicity risks potentially associated with switching among therapeutic proteins

In each case, Professor Trifirò provided appropriate evidence and explanation as to why these myths should not be considered a concern.

Challenges related to physicochemical characterization and analytical comparability of biologicals/biosimilars
Mohammad A Alsenaidy, Assistant Professor at KSU, described biologicals/biosimilars as structurally complex, highly specific macromolecules used therapeutically to compensate for body deficiencies, e.g. hormones and clotting factors; and to treat diseases, e.g. cytokines and monoclonal antibodies; and to prevent illnesses, e.g. polyclonal antiserum and certain vaccines. He noted that the structural complexity of proteins makes it challenging to preserve their conformational integrity, biological activity and stability throughout manufacturing, storage and distribution. Professor Alsenaidy then discussed how physiochemical characterizations, stability and degradation profiles of protein-based drugs can be carried out. These are key exercises for the development of protein-based drugs, whether originator or biosimilar. He also noted that, the ability to establish high quality analytical profiles determines the extent for additional animal and/or clinical evaluations such as pharmacokinetics (PK), pharmacodynamics (PD), and/or immunogenicity studies.

Biosimilar cell line development
Musaed Abdullah Alkholief, Assistant Professor at KSU, outlined the key factors necessary for successful biosimilar cell line development. He noted that during the upstream development of these molecules, cell line selection and cell culture processing represents the most critical step in biosimilar development and as such should be carefully evaluated. When developing a biosimilar the slightest variability between the originator cell line and the biosimilar cell line may significantly affect the characteristics of the product, consequently limiting its utilization. It is anticipated that by 2022 the global market size of cell line development will reach US$6 billion. In conclusion, Professor Alkholief noted that a better understanding of the current status and future directions of cell line development is needed to fully exploit biosimilar development processes.

Biosimilar regulations in Saudi Arabia
The Executive Director for Pharmaceutical Products Evaluation of the Saudi Food and Drug Administration (SFDA), Dr Ali M Alhomaidan, gave a talk in which he described the biosimilar approval pathway in Saudi Arabia, quality, safety and efficacy considerations surrounding biosimilars, and their pricing and interchangeability. Background on the pricing of biosimilars in Saudi Arabia and the system used for pricing these products is explained in the paper by Alhomaidan et al. [7]. Further information can be found in the summary of discussions of this meeting below.

Interchangeability for biosimilars: considerations and concerns
Aws Alshamsan, Associate Professor at KSU, discussed the concepts of interchangeability, switching and substitution of biosimilars, and how they differ across Europe, Saudi Arabia and the US. He highlighted that a number of concerns surround the regulatory authority definitions and the differences between them. In addition, he highlighted four key challenges that need to be overcome to facilitate interchangeability that is safe and efficacious. These include: the extrapolation to indications only studied for the reference product; ethical and medical–legal aspects of approval; developing strategies for adequate post-marketing pharmacovigilance; and developing effective pricing policy that distinguishes high quality products.

Formulary considerations for biosimilars for health systems
According to Professor Ahmed Al-jedai of Alfaisal University, Saudi Arabia, global spending on medicinal products is expected to reach Euros 1.3 trillion by 2020 and that, with price reductions of 20%–40% with respect to reference products, biosimilars could create an estimated cumulative savings of Euros 50–100 billion during this timeframe. He highlighted the differences in biosimilar approval approaches between Europe and the US and noted that SFDA and the GCC have adopted the European Medicines Agency’s (EMA) approach. Currently, only five biosimilars are available in the Saudi markets. He also outlined the cost analysis of the biosimilars already approved in Saudi Arabia and discussed the role that pharmacists can play in increasing biosimilar adoption.

Switching from originator product to biosimilars in rheumatology, dermatology and gastroenterology: clinical evidence
The keynote presentation was delivered by Tore Kvien, Professor of Medicine and Rheumatology at Diakonhjemmet Hospital in Norway. This presentation outlined the current need for biosimilar products that are less expensive and as such, can increase patient access to biological medicines. The details of a randomized clinical trial that compared the tumour necrosis factor (TNF) inhibitor infliximab with the less expensive biosimilar CT-P13, also known as the NOR-SWITCH study [8], were presented. This study addressed questions surrounding the efficacy, safety and immunogenicity of switching from an originator to its biosimilar for the first time and showed that switching is not inferior to remaining with the originator product, and that switching can be considered for non-medical reasons.

During a 6-month extension study, patients on the reference infliximab were switched to CT-P13 and compared to the group whose treatment with CT-P13 was maintained. Results from the switch group was not inferior to the maintenance group. The point estimates were actually generally in favour of the switch group and this extension study supported the results of the primary study published in The Lancet 2017.

Oncologist perspective – the use of biosimilar trastuzumab in breast cancer: clinical experience
Assistant Professor Meteb Al-Foheidi of King Saud Bin Abdulaziz University for Health Science in Saudi Arabia discussed the need for oncology biosimilars, noting that they could lead to cancer treatment savings of up to 30%. However, there is currently no consensus on which endpoints to use in oncology biosimilar studies and long-term endpoints are often not feasible in these studies.

Professor Al-Foheidi also described the case of biosimilar trastuzumab in breast cancer treatment and noted that there had been no issues or safety concerns regarding its use in the EU.

Summary of the discussions that followed the expert presentations

After the presentations, there was the opportunity for discussion about the topics covered. The key discussion points are summarized below.

Biosimilar variability
The presentation on ‘Biosimilar cell line development’ prompted a number of questions about biosimilar product variability. Assistant Professor Alkholief stressed that when developing a biosimilar the most critical step is choosing the initial cell line. Having the right components and conditions for growth is also very important in reducing variability, but these are all dependent on the cell line chosen to begin with.

It was suggested that a ‘cell line bank’ could be used as a reservoir of standard cell lines. However, he noted that cell lines are already available to buy and that this is not the critical issue affecting variability. Instead, pharmaceutical companies develop their own processes and set the conditions to grow the biologicals/biosimilars as required and the pharmaceutical companies are not required to share this information at any point, even after patent expiry. As such, variability is inevitable for biosimilars as cell lines and conditions will likely differ from those used to produce the reference products. Despite this, Professor Aws Alshamsan informed that the World Health Organization (WHO) is starting a programme to create a master cell line of bevacizumab so that it can be distributed to manufacturers in order to harmonize biosimilar product outcomes. Dr Ibrahim Aljuffali from the Ministry of Health Saudi Arabia advised that this was done in an attempt to reduce the cost of biosimilars and lessen the burden on national healthcare budgets. He also stated that this, and other similar cell lines, are likely to have a significant impact on the biosimilar landscape in the future.

The cell line bank approach could be rolled out to produce other biologicals after their patents have expired. Such banks would enable governmental agencies to harmonize globally by providing the starting material. However, such an initiative is the responsibility of the government regulators and not private companies.

Global harmonization of biosimilar regulatory approval procedures
Across the globe, biosimilar approval processes differ and harmonizing these processes could reduce the number of clinical studies carried out and make biosimilars more accessible. However, achieving global harmonization of regulation and approval procedures for biosimilars is likely to be complicated and lengthy.

Professor Trifirò highlighted that EMA and the US Food and Drug Administration (FDA), who have differing policies, regularly communicate regarding approval of biosimilar products. However, having different policies in different countries can reduce the credibility of biosimilars and the amount of trust practitioners and patients have in these products. For example, in the case of infliximab, which underwent studies verifying its use as a treatment option for rheumatology indications, the biosimilar drug product was also approved for treatment of inflammatory bowel disease (IBD) in Europe based on extrapolation of indication. Nevertheless, this extrapolation was not accepted by Health Canada and these contradicting policies may lead physicians to have a lack of confidence in the biosimilar product.

A lack of harmonization does not only cause a lack of trust in biosimilar products, but it also creates an increased workload for pharmaceutical manufacturers. They have to submit applications to different regulatory authorities worldwide which have different requirements and this means separate bioequivalence studies and applications are needed. This is expensive for producers in terms of both time and money.

Currently, there is no global harmonization for the regulation and approval of generic drug products. ‘These are far simpler than biologicals/biosimilars and as such, consensus is that we will not see global harmonization of biosimilars for some time. However, biosimilar regulation development is at an early stage in some countries and there are still only relatively few products approved globally, which means that regulatory processes can still be altered and developed to allow for harmonization’, said Professor Trifirò.

Biosimilar pricing
Biosimilars are designed to be lower-cost alternatives to originator products and facilitate access to biological medicines worldwide. Professor Kvien advised that in most markets, the cost reduction for the biosimilar infliximab is 30%. In Norway, when Remsima was approved it was initially 39% less expensive than the originator Remicade, in its second year it was 69% less expensive (possibly the highest cost reduction seen so far), and it is currently about 60% cheaper. This large cost reduction was largely achievable due to the Norwegian national tender system.

In Saudi Arabia, the price of each registered product is accessible through the SFDA website. Dr Alhomaidan described how biosimilar prices are set in Saudi Arabia according to three approaches and each product is priced on a case-by-case basis. The first pricing approach is based on reference pricing, where the price is set relative to its price in 30 reference countries. The second approach requires pharmacoeconomic evaluation and the price is set according to the results of this. And, the third is based on recommendations from the company/manufacturer. In the latter case, the company recommendation may be applied if it offers a product at a significantly lower price than reference product prices.

Professor Kvien added that the pricing transparency in Saudi Arabia is positive. In Europe, pricing can be concealed, but he believes that patients should be aware of the magnitude of saving that is achieved when choosing to switch to a biosimilar product.

The discussion highlighted that in some cases, a reference product manufacturer will gain biosimilar market access after originator patent expiry through production and marketing of a subsidiary’s biosimilar. In these cases, Professor Al-jedai believes that it is highly likely that some biosimilars will come from the same cell line as the reference products as several major pharmaceutical companies have started producing biosimilars of their own biological products. It would cost pharmaceutical companies and its subsidiaries a lot in terms of time and money, to start from scratch and create a new biosimilar when they know they already have a functioning and effective cell line that produces the already approved medicine. Under these circumstances, Professor Kvien believes the product is the same as the originator but re-packaged to be able to take a share of the biosimilar market. Here, the biosimilar must still undergo the same process of evaluation and approval of any other biosimilar product.

Biosimilar nomenclature
Much debate has surrounded the nomenclature of biosimilars in recent years. Across the globe, different approaches have been adopted. With respect to this, Professor Trifirò emphasized that traceability is key for any biological/biosimilar/chemical drug product. It should be possible to achieve this through product naming or identification via batch number. If products can be traced back to the batch level or at least brand name, adequate pharmacovigilance will be achieved so that the source of any adverse reactions/effects can be immediately identified.

In Europe, legislation has been passed to improve pharmacovigilance. In the event of an adverse event, the brand name must be evident (this differs for each biosimilar version of a reference product); and in the absence of a brand name, the manufacturer and non-proprietary name, plus batch level information, must be available. This is very important if a quality investigation is required.

In the US, the situation is slightly different. All biosimilar versions of a reference product currently have the same non-proprietary name which makes them indistinguishable from one another. With respect to this, it is also noted that if one company’s biosimilar product is flagged as a concern, this affects the credibility of all biosimilars with the same non-proprietary name, even if they are made by different manufacturers.

To address this problem and improve traceability of biosimilars, FDA implements a non-proprietary name policy with a four-lowercase letter suffix [9]. This aims to improve and facilitate pharmacovigilance in a multi-source environment which will prevent adverse event data collection that cannot be disaggregated. It should be possible to disaggregate all data and have product-level traceability that allows manufacturers to be held accountable and to develop product safety signalling. In addition to this, FDA’s new naming approach hopes to prevent inadvertent substitutions occurring as a result of product names being the same. This can occur at the pharmacy, rather than prescriber level, if non-proprietary names are shared by different products. At present, when two products have the same non-proprietary name, they can be perceived as being therapeutically equivalents. However, for biologicals and biosimilars, healthcare professionals need to examine the trial data to confirm that they are therapeutically similar and ensure a switch is acceptable.

Dr Aljuffali noted that the new naming guideline issued by FDA is likely to cause chaos and confusion. The idea is that approved products will be named retrospectively and as such, there will be significant impact on electronic health records, utilization of products, existing national drug codification, and finances. Dr Hajer Almudaiheem of the Ministry of Health Saudi Arabia agrees that the new US naming guideline will cause confusion. She also added that if products have different names this could create an artificial barrier to interchangeability due to the misperceptions of prescribers/practitioners.

Professor Trifirò emphasized that it is important to reach a balance in which nomenclature allows the traceability of products and also facilitates the interchangeability of drug products to ensure effective pharmacovigilance.

There are various other naming approaches being adopted around the world. Overall, this makes it difficult to assemble adverse event data in a manner that can be used and accessed internationally. A globally harmonized naming approach for biologicals/biosimilars would facilitate universal pharmacovigilance.

Patient choice, nocebo effect and education on biosimilars
In the future, it is hoped that patients will have a far greater role when it comes to decisions made about their treatment. However, ‘In Saudi Arabia, patients do not yet have this level of autonomy regarding their treatment and their physician makes most of the treatment decisions on their behalf’, said Professor Alshamsan. He stressed that this is likely a cultural issue governed by patient attitudes in GCC countries that are different to those seen in the west.

Professor Al-Foheidi reiterated that in Saudi Arabia the healthcare provider is generally in charge of treatment and switching. Here, both the practitioner and pharmacist have a say in the ultimate treatment decision. Clinicians weigh up the benefits and risks of treatment options based on the information available to them and although they may discuss this with patients, ultimately clinicians make the decision.

‘Patients should always be fully informed about their treatment options and decisions made by their clinicians. Through adequate patient education, the nocebo effect can be dramatically reduced’, said Professor Kvien.

This final comment was supported by Dr Nabila Al Lawati who noted that generally, patients are either educated or non-educated with respect to biosimilars and it is relatively easy to persuade the educated patients to take biosimilars. However, non-educated patients, particularly those who are older, often believe that the most expensive medication is the best and in such cases; it may be beneficial to leave the decision in the hands of the clinician. Professor Al-Foheidi commented that it can be more effective to make a general rather than an individual decision regarding biosimilars and patient advocacies can play an important role here.

Biological/biosimilar switching
The issue of switching between biologicals and biosimilars and the safety of multi-switching was raised. Professor Trifirò advised that the pre- and post-marketing evidence gathered so far, with respect to switching from different sources, had not identified any clinical issues. In Europe, a lot of data have been accumulated which allow for the assessment of the long-term effects of switching, however, this is difficult to investigate in a post-marketing setting. He added that ideally, studies similar to the NOR-SWITCH study [8] for each biosimilar would be carried out, but in reality performing such expensive RCT (randomized clinical trials) to explore all possible reference product/biosimilar switches is impossible. So, efforts need to be made to investigate the effects on long-term switching especially for drugs that have long-term effects, such as rituximab in real-world settings. He noted that healthcare databases including claims databases and electronic medical records as well as drug registries have the potential to help here. Understanding the long-term effects of switching and multi-switching between biosimilars is one of the key challenges that needs to be addressed and this requires an international concerted effort to develop the best methodological approach.

Professor Kvien informed about the Norwegian disease-modifying antirheumatic drugs (DMARD) registry established in 2000. The registry continues to enrol patients who are switching to a biosimilar and those starting treatment with a biosimilar. He estimates that 80% of patients using biosimilars enrol with the registry. However, more data are needed to conduct analysis of biosimilars in a way similar to that carried out in the NOR-SWITCH trial [8]. This registry will soon merge with other registries, such as the death and cancer registries, so that there is more robust data on safety.

Biosimilars in Saudi Arabia
Dr Alhomaidan confirmed that in Saudi Arabia there are guidelines on the quality requirements for biosimilars and there is a pricing system in development for biosimilars, but this is not well established yet. The safety and efficacy requirements are the same as those adopted by EMA. In both Europe and Saudi Arabia, guidelines do not aim to promote biosimilar usage, but instead promote the dissemination of the correct information about them to ensure their quality, safety and efficacy.

In Saudi Arabia, biosimilar products are evaluated during registration, with the first consignment, and then are continually assessed by taking random market samples. When it comes to manufacturer inspections, each manufacturer is inspected by a team of three inspectors before biosimilar production is initiated. He added that Saudi Arabia is in the process of setting up a centre that will enable phase I clinical trials to be carried out by an approved, licensed clinical trials team. These will subsequently be reviewed by the benefit-risk assessment team to facilitate the safe and efficacious entry of biosimilars to the market.

Action points highlighted in the discussions
The key findings from the discussions of the stakeholder meeting are summarized as below:

Further research and investment into ‘master cell bank’ could enable further cost reductions in biosimilar products and reduce variability between products and batches.
Action needs to be taken to achieve global harmonization of biosimilar approval and regulation procedures. This should be done in the near future, while currently there are only few products approved in the global market.
Biosimilar pricing transparency is positive and should continue.
Action should be taken to ensure that all biosimilar products globally are traceable to batch level to ensure adequate pharmacovigilance is upheld.
Global consistency, transferability and/or harmonization of biosimilar nomenclature needs to be achieved.
Strong governmental regulations should be in place to ensure drug products can be tracked without necessarily having to initiate new biosimilar nomenclature.
The long-term effects of switching and multi-switching between biosimilars and/or reference products need to be addressed. This requires an international concerted effort to develop an optimal methodological approach.
Electronic healthcare records need to be developed and implemented to facilitate pharmacovigilance and gather further data on switching.
Biosimilar patient registries could be established and implemented to gather further data on switching.

Parallel case study working sessions

After the formal presentations and discussions, the audience was presented with data for two semi-fictional SBPs, both are a trastuzumab monoclonal antibody. The participants were divided into two discussion groups where they evaluated the fictional data supplied. This was carried out in a similar way to that which occurred at previous GaBI meetings [2].

Summary discussion of case study of therapeutic protein monoclonal antibody – candidate 1
Based on the information the two groups received, Dr Nabila Jawad Al Lawati and Associate Professor Khalid Alsaleh agreed that the first candidate, monoclonal antibody IgG1, did qualify as a biosimilar of the reference product. Dr Al Lawati noted that, with respect to the physiochemical attributes, the charge profile acidity and deamination were not similar to the originator, but this did not affect the products activity or quality attributes. In terms of biological attributes, all is within predefined limits, so the candidate does qualify as a biosimilar from a quality perspective. Professor Alsaleh noted that his discussion group was aware that there are some differences between the candidate and the reference product, but these were not major.

To remediate the differences between the IgG1 candidate and the biosimilar, Dr Al Lawati’s group thought that the product applicant could be asked to alter the charge profile to ensure it is more acidic. Professor Alsaleh’s group said the chemical structure of the candidate could be altered but this would then need further biosimilarity studies to be carried out on it which would negate the point in developing a biosimilar as it would cost a lot in terms of time and money.

To address the ‘residual uncertainty’ in the preclinical and/or clinical studies, Dr Al Lawati’s group suggested that the PK/PD parameters be obtained in clinical studies. Professor Alsaleh’s group said that the bio-immunogenicity could be addressed through clinical studies. Here, the group noted that there was a hard endpoint observable when using the biosimilar. This was seen in the complete initial pathological response when treatment was given, and in the follow-up studies carried out in the year after initial treatment. The overall response to the treatment was good – 46% for the candidate versus 48% for the reference product.

Dr Al Lawati’s group said that, for extrapolation to be recommended, the applicant would need to submit more information about the mechanism of action and site of action. Only with this additional information could a decision be made. On the other hand, Professor Alsaleh’s group said that the IgG1 candidate could be extrapolated but only if there was no other choice. However, if the reference product was available this would be used in preference to the biosimilar for extrapolated indications. He explained that for the reference product trastuzumab, there is a combination indication for metastatic settings which makes extrapolation complicated. He noted that, if a trastuzumab, biosimilar were to be used in such a situation, a combination study should be required, not just clinical data.

Summary discussion of case study of therapeutic protein monoclonal antibody – candidate 2
Based on the information the two groups received, Dr Al Lawati and Professor Alsaleh agreed that the second candidate did not qualify as a biosimilar of the reference product as there8 were many differences in the physiochemical properties of the candidate and the originator. Dr Al Lawati noted that there were particularly significant differences in the total protein content which is an important parameter. The charge profile and deamination also differed. In addition, there were differences in the aggregates and particulates which are important factors when considering the immunogenicity.

Dr Al Lawati said that the physiochemical data need to be a closer match to those of the reference product before further steps are taken towards candidate approval. According to Professor Alsaleh, there is a very soft endpoint to the study that should not generally be used as a primary endpoint and this needs to be amended. Based on the physiochemical data, both groups agreed that the candidate should not undergo preclinical/clinical trials at this point. As the candidate is not a suitable biosimilar, it cannot be extrapolated for any indications.

Conclusion

Biosimilar medicines are being increasingly used and available across GCC countries. The first GCC meeting was successful in bringing representatives from GCC nations together with experts from Europe, Saudi Arabia and the US, to discuss the best routes forward for successful biosimilar approval and regulation and enabled action points to facilitate biosimilar uptake with appropriate pharmacovigilance to be outlined.

Speaker Faculty and Moderators

Speakers
Assistant Professor Meteb Al-Foheidi, MD, FRCPC, Saudi Arabia
Assistant Professor Khalid A Alburikan, PharmD, BCPS, Saudi Arabia
Ali M Alhomaidan, PhD, Saudi Arabia
Assistant Professor Abdulaziz Alhossan, PharmD, MPH, BCPS, Saudi Arabia
Professor Ahmed H Al-jedai, PharmD, MBA, BCPS, FCCP, FAST, Saudi Arabia
Assistant Professor Musaed Abdullah Alkholief, PhD, Saudi Arabia
Assistant Professor Mohammad A Alsenaidy, MSc, PhD, Saudi Arabia
Professor Aws Alshamsan, BPharm, RPh, PhD, Saudi Arabia
Thomas Felix, MD, USA
John Bradley Jordan, PhD, USA
Professor Tore Kristian Kvien, MD, PhD, Norway
Professor Gianluca Trifirò, MD, PhD, Italy

Moderators
Nabila Jawad Al Lawati, PhD, Oman
Associate Professor Khalid Alsaleh, MD, Saudi Arabia

Editor’s comment

All moderators had provided the discussion/conclusion of the group discussion, read the report and revised the content of the summary discussion of the case study.

Acknowledgements

The Generics and Biosimilars Initiative (GaBI) wishes to thank Assistant Professor Abdulaziz Alhossan, for his support through the offering of advice and information during the preparation of this scientific meeting; as well as Professor Gianluca Trifirò, chair of the 2017 GCC stakeholder meeting; for his strong support in facilitating the discussion in the scientific meeting.

The authors and speakers would like to acknowledge the help of all the meeting speaker faculty and participants, each of whom contributed to the success of the meeting and the content of this report, as well as the support of the moderators: Dr Nabila Jawad Al Lawati and Associate Professor Khalid Alsaleh in facilitating meaningful discussion during the parallel case study working sessions, presenting the discussion findings at the meeting and contributing in the finalization of this Meeting Report.

Lastly, the authors wish to thank Ms Alice Rolandini Jensen, GaBI Journal Editor, in preparing and finalizing this meeting report manuscript and providing English editing support on the group summaries.

Competing interests: The scientific meeting was sponsored by an unrestricted educational grant to GaBI from Amgen Inc.

Provenance and peer review: Not commissioned; externally peer reviewed.

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Author for correspondence: Professor Gianluca Trifirò, MD, PhD, Policlinico ‘G Martino’, Dipartimento di Medicina, Clinica e Sperimentale, 1 Via Consolare Valeria, IT-98125 Messina, Italy.

Disclosure of Conflict of Interest Statement is available upon request.

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