Category: Abstracted Scientific Content

Submitted: 15 March 2021; Revised: 17 March 2021; Accepted: 18 March 2021; Published online first: 24 March 2021

Cancer is one of the leading causes of mortality in the world today. The development of new drugs can reduce death rates, but these products are extremely expensive in terms of development time and money. This has led to the strategy of drug repurposing; whereby drug products already approved for noncancer indications are identified as potential cancer therapies. A review, published in Signal Transduction and Targeted Therapy [1], presents various promising repurposed non-oncology drugs for clinical cancer management.

The study also summarizes approaches used for drug repurposing and discusses the main barriers to uptake [2].

Drug repurposing and cancer treatment: an overview

When an already approved drug product is repurposed, pharmacokinetic, pharmacodynamic, and toxicity profiles of drugs have been already established in preclinical and phase I clinical studies. These drugs can thus rapidly progress to phase II and phase III clinical studies and the associated development time and cost of the cancer treatment can be significantly reduced.

The study notes that our understanding of cancer biology and the associated characteristics of cancer is increasing. If this is successfully coupled with repurposing studies that apply systematic screening of the entire pharmacopoeia together with advanced bioinformatics, new drugs for cancer treatment can be identified faster and at reduced cost.

The study provides a summary of non-oncology compounds that are already used for cancer therapy which are outlined below. It highlights the specific cancer characteristics targeted and distinguishes between those agents suitable for monotherapy or as drug combinations. For all the treatment options outlined, the study also provides a detailed discussion of how they effectively regulate at least one characteristic of cancer; or exert comprehensive anticancer effects by regulating multiple targets mediated by various alternative signalling routes.

Non-oncology drugs suitable for cancer monotherapy

Proliferative signal inhibitors
Cancer cells have an ability to maintain chronic proliferation. Non-oncology drugs which work by inhibiting proliferative signalling include rapamycin, prazosin, indomethacin. These had original applications as an immunosuppressant and anti-restenosis agent; in hypertension; and in rheumatic disease, respectively.

Cancer cell death inducers
Apoptosis causes cell death and prevents tumourigenesis once the cell is damaged or is placed under various physiologic stresses. Non-oncology drugs which work by inducing cell death include artemisinin, chloroquine and their related derivatives. Both of these medications are used to treat malaria and chloroquine is also a treatment for rheumatoid arthritis.

Cellular metabolism regulators
Cancer cells often have reprogrammed energy metabolism which supports malignancy by sustaining key characteristics of cancer, including uncontrolled cell proliferation, evading growth suppressors, and resisting cell death. Non-oncology drugs which work by regulating of cellular metabolism include etformin and disulfiram. The former is used to treat obese type-2 diabetes and the latter is an alcohol aversion drug.

Antitumour immunity activators
Some cancers, especially virus-induced cancers, can avoid immune surveillance or limit being eliminated by the immune system by somehow regulating both the innate and adaptive immune systems. Non-oncology drugs which work by activation of antitumour immunity include infectious disease vaccines:

Non-oncology drugs suitable for drug combination therapy

The study notes that, in some cases, compounds may not be considered for drug repurposing screening due to their low anticancer activity at known tolerated plasma drug doses described in previous indications. However, drugs that may be effective at higher dosage can be utilized through drug combination therapy. Here, a synergistic effect is produced by targeting alternative signalling pathways associated with certain cancer characteristics.

Tumour suppressor reactivators
There is now a bank of evidence that indicates a lack of crucial tumour suppressors can stimulate tumour growth. Many non-oncology drugs are being repurposed to target cancer cells that evade growth suppressors. Non-oncology drugs which work by reactivating growth suppressors include quinacrine and ritonavir. The former has previous indications for malaria, giardiasis, rheumatoid arthritis, and the latter for human immunodeficiency virus (HIV) treatment.

Cancer cell division interrupters
In cancer cells, the specialized DNA polymerase, telomerase, is expressed at high levels to counteract the normal cell growth and the division cycle. Non-oncology drugs which work by targeting telomerase and interfering with replication include curcumin, used to treat dermatological diseases, and genistein, used in the treatment of the menopause, osteoporosis and obesity.

Angiogenesis reducers
Tumour cells also stimulate angiogenesis to generate neovasculature, an important mechanism by which tumours obtain nutrients and evacuate waste products. Non-oncology drugs which work by decreasing angiogenesis include the infamous thalidomide, originally used to treat the symptoms of morning sickness, which is now used as a sedative and antiemetic drug; and itraconazole, an antifungal agent.

Cell invasion and metastasis suppressors
Tumour invasion is the mechanism by which tumour cells spread to the surrounding environment, while tumour metastasis is where cancer cells leave the primary tumour and migrate to a new location where they generate new (secondary) tumours. Some non-oncology drugs work by suppression of invasion and metastasis. These include Barberine, used to treat bacterial diarrhoea and niclosamide, an antihelminthic drug.

Genome instability disruptors
Genome instability is a major characteristic of malignancy. This allows some favourable mutant tumour genotypes to survive under stress conditions, particularly those induced by traditional cancer treatment methods, such as chemo- and radiotherapy. As such, to enhance the therapeutic index of traditional cancer therapies, drugs could be repurposed as sensitizers of genotoxic therapy to inhibit DNA damage response. Non-oncology drugs which work by disrupting the DNA damage response include spironolactone and mebendazole, which are respectively diuretic and antihelminthic drugs.

Tumour-promoting inflammation reducers
Inflammation is typically associated with tumourigenesis as it supports and accelerates tumour growth. Some non-oncology drugs work by targeting tumour-promoting inflammation. These include aspirin, a common pain and fever relief medication, and thiocolchicoside, used to treat rheumatologic and orthopaedic disorders.

Conclusions
The study stresses the urgent need to develop effective, safe, cheaper, and readily available anticancer agents. The repurposed drugs outlined that act on specific characteristics of cancer, show that there is therapeutic potential in this strategy.

Editor’s note
Oncology drugs
Proliferative signal inhibitors, cancer cell death inducers, cellular metabolism regulators, antitumour immunity activators,

Non-oncology drugs suitable for drug combination therapy
Tumour suppressor reactivators, cancer cell division interrupters, angiogenesis reducers, cell invasion and metastasis suppressors, genome instability disruptors, and tumour-promoting inflammation reducers

Competing interests: The work of the paper [1] was supported by grants from the Chinese NSFC (nos. 81821002, 81790251, and 81773143), and Guangdong Basic and Applied Basic Research Foundation (2019B030302012).

Provenance and peer review: Article abstracted based on published scientific or research papers recommended by members of the Editorial Board; internally peer reviewed.

Alice Rolandini Jensen, MSci, GaBI Journal Editor

References
1. Zhang Z, Zhou L, Xie N, Nice EC, Zhang T, Cui , et al. Overcoming cancer therapeutic bottleneck by drug repurposing. Signal Transduct Target Ther. 2020;5(1):113.
2. GaBI Online – Generics and Biosimilars Initiative. Technological approaches to drug repurposing for cancer treatment [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2021 Mar 17]. Available from: www.gabionline.net/Generics/Research/Technological-approaches-to-drug-repurposing-for-cancer-treatment

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2021 Pro Pharma Communications International

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.

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Submitted: 6 December 2018; Revised: 12 December 2018; Accepted: 14 December 2018; Published online first: 19 December 2018

Generic drugs are currently central to disease treatment in the US. However, recent policy concerns have focussed on generics supply inadequacies and the perceived increase in prices of some generic drug products. To further explore the changing landscape of US generic prescription drug markets, a study published by the National Bureau of Economic Research (NBER) in the US examines manufacturer entry and exit, the extent of competition and the relationship between supply structure and inflation adjusted prices among generic drugs, between 2004–2016 [1].

In recent years, policy developments in the US have resulted in a shift towards generic drug use. Their share of all retail and mail order dispensed drugs increased from 36% in 1994 to 87% in 2015. In their early years following inception, generic drug products largely provided increased access to safe and effective treatments at prices that continued to decrease. However, after 2009, the prices of some generics started to increase for a number of reasons. It is posited that these include low generics profit margins, concentrated buying power, and pharmaceutical plants failing to meet standards set out by the US Food and Drug Administration (FDA). Since 2012, massive price increases of generics have been observed.

With this in mind, the authors of the study who are based at NBER, sought to answer the following questions: ‘How competitive are markets for generic drugs?’, and ‘How has the competitive market structure varied over time and across drug formulations and therapeutic classes?’. To do this and better understand the landscape of generic prescription drugs in the US, they conducted an empirical evaluation using national quarterly data from QuintilesIMS’s National Sales Perspectives^™ (NSP) database between 2004 Q4 and 2016 Q3, on US prescription drug sales. They undertook several descriptive and statistical analyses.

Overall, the team found that between 2004–2016, approximately 500–650 manufacturers supplied prescription drugs (with a steady increase over this period).

Total annual sales revenue derived by both brand and generics manufacturers increased substantially over time, from approximately US$300 billion in 2004 to US$450 billion in 2016. The study found that there was a statistically significant increase in the price of generics in the US over time. This became particularly evident following the implementation of the 2010 Affordable Care Act (ACA) and the 2012 Generic Drug User Fee Amendments (GDUFA I). There was a positive correlation between price increase and the reduction in generics manufacturers over time. Their analyses also isolated four sets of important novel findings relevant to the US generics markets which are summarized in the following sections.

Small generics markets

Through defining the product market by molecule dosage form (that may be manufactured or marketed by multiple suppliers), the team found that the size of generics markets are surprisingly small. Here, the median sizes of drug markets have inflation adjusted sales revenues starting under US$10 million per annum but increasing over time.

Generic entry and exit rates have differing time trends

The number and rate of generic drug products entering the market increased up to 2013, after which they decreased. In contrast, the number and rate of generic drug products exiting has continually increased over time.

Decreasing number of generics manufacturers

The evaluation showed that the median number of generics manufacturers in each market is approximately two and the mean approximately four. Authors of the study consider these numbers to be relatively low. Their evaluation also provides evidence suggesting that there have been decreasing numbers of generic drug suppliers/manufacturers between 2004–2016, particularly following implementation of the Affordable Care Act (ACA) and Generic Drug User Fee Amendments (GDUFA I), both of which have contributed to more drug exits and less entries over time. In addition, evidence suggests that approximately 40 per cent of markets are supplied by just one generics manufacturer. In regard to this, it was also found that there are likely to be two or fewer suppliers of non-oral formulations of generic drugs, whereas for oral formulations are likely to have more suppliers.

Low levels of competition in the generics market

The level of competition in the generics market between 2004–2016 was determined by calculating the Herfindahl-Hirschman Index (HHI), a measure of market concentration. In this case, market concentration is the extent to which sales in a drugs market are dominated by one or more manufacturers. During the study period, the team’s analysis showed a decline in concentration for most therapeutic classes of generic drugs. As such, the HHI values indicate distinctly low levels of competition between manufacturers of generic drug products.

Monopolies reign over US generics

As a result of these findings, the authors conclude that the US generic drugs market is in a relatively steady state with low levels of competition between generics manufactures. This contrasts with previous assumptions and published works that assume a high level of competition involving four or more competitors following patent expiry of originator molecules. The generic drugs market is made up of relatively small revenue products that have a monopoly, or at most a duopoly. The authors note that, considering the lack of competition, it is perhaps surprising that the price of generics has not risen further.

The study concludes with a summary of a number of testable hypotheses based on economic theory that may explain the US generics landscape observed. The authors encourage further investigation of these hypotheses in order to better understand generics markets and the impact of policy on keeping products affordable.

Competing interests: None.

Provenance and peer review: Article abstracted based on published scientific or research papers recommended by members of the Editorial Board; internally peer reviewed.

Alice Rolandini Jensen, MSci, GaBI Journal Editor

Reference
1. Berndt ER, Conti RM, Murphy SJ. The landscape of US generic prescription drug markets, 2004–2016. NBER Working Paper No. 23640.

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2018 Pro Pharma Communications International

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.

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Submitted: 21 November 2018; Revised: 22 November 2018; Accepted: 28 November 2018; Published online first: 4 December 2018

A study published by the World Health Organization (WHO) compares the effect of different pricing policies for generic medicines in four countries [1]. Using atorvastatin as a case study, their results show that price cuts combined with price-disclosure policies lead to lasting price reductions, while price cuts alone are less effective over the long term.

There are a range of policies available to facilitate the use of generic drugs, such as mandatory generics substitution, where pharmacists must, where possible, substitute a generic drug product for a branded one; reference pricing, where the price of a generic drug is set based on similar medicines; and percentage price reductions, where the price of the generic drug is reduced by a set amount over time. However, little is known about how these policies actually influence the price of generic drugs over time.

This study investigated this issue in the context of atorvastatin, a cholesterol lowering drug marketed by Pfizer as ‘Lipitor’ and the world’s best-selling medication between 1996 and 2012.

Using Australia, New Zealand, the Republic of Korea (South Korea) and Singapore as case studies, the researched evaluated the annual price of atorvastatin, per defined daily dose (DDD, the assumed average maintenance dose per day) supplied, across each country.

They assessed data between 2006 (two years before the generic drug was introduced in all countries) and 2015 (four years after the generic drug was introduced).

Each country uses a slightly different pricing policy. In New Zealand for example, the government applies a tendering system, whereby the market is typically limited to one brand, alongside the use of preferred medicines, which means a subsidy is offered for just one or two medicines within a class.

Before generic atorvastatin reached the market, New Zealand had the lowest price for the drug (just US$0.10/DDD), while the Republic of Korea had a price almost 30 times that (US$2.89/DDD).

The Republic of Korea mandates a 30% reduction in the price of an originator drug the year after patent expiry. The first generic drug product to enter the market is priced 15% below the originator, with a further 10% reduction in both the originator and generic medicine one year after generics entry.

As expected, prices fell in all countries when generic atorvastatin was introduced – except in New Zealand, where prices were already remarkably low. The biggest drop in price after generic entry was in Singapore, where prices decreased by almost 50% in the first year after the generic entered the market. Singapore operates free pricing for manufacturers in the private market, while there is competitive tendering in the public sector. Although there is no mandatory generic substitution in Singapore, public sector institutions are encouraged to use generic drugs.

Four years after generic atorvastatin was introduced, the price had fallen in all countries, however, there were still significant price differences between countries. Prices in New Zealand remained the lowest (US$0.03/DDD) and highest in Korea (US$1.43/DDD). In the middle of the range were Australia (US$0.14/DDD) and Singapore (US$0.47/DDD).

The authors relate these price differences to policy. They suggest that the competitive tendering system utilized by New Zealand is most effective at reducing prices and led to low prices for atorvastatin even before Pfizer’s patent had expired.

However, because prices were already low in New Zealand, they did not decrease after generic versions entered the market.

Pricing policies in Australia, Korea and Singapore were more impactful after the generic entered the market and prices reduced in all countries within four years of generics entry. Prices for atorvastatin decreased by as much as 80% in Australia and Singapore, compared to just 46% in Korea.

Singapore, like New Zealand, employs a tendering system, while Australia applies mandatory price cuts on generic entry combined with price-disclosure policies. Korea meanwhile employs mandatory price cuts alone. This led to immediate price reductions for atorvastatin (25% in the first year) but the impact of this policy was not enduring, and was associated with the smallest price reduction after four years. Overall then, this study suggests that a mix of strategies for pricing generic medicines are most effective and can maximise value for money.

Competing interests: None.

Provenance and peer review: Article abstracted based on published scientific or research papers recommended by members of the Editorial Board; internally peer reviewed.

Eleanor Bird, MSc, GaBI Journal Editor

Reference
1. Roughead EE, Kim DS, Ong B, Kemp-Casey A. Pricing policies for generic medicines in Australia, New Zealand, the Republic of Korea and Singapore: patent expiry and influence on atorvastatin price. WHO South East Asia J Public Health. 2018;7(2):99-106.

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2018 Pro Pharma Communications International

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.

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Submitted: 20 June 2018; Revised: 14 August 2018; Accepted: 18 August 2018; Published online first: 31 August 2018

The ageing population, longer life expectancies, and the increasing cost of drugs are expected to significantly increase the burden on healthcare systems in the coming years. To reduce this burden and increase access to new, innovative and effective drugs in the European Union (EU), risk-sharing agreements (RSAs) between national healthcare payers, health technology assessment (HTA) agencies and the pharmaceutical industry, have been put in place. A recent study published in PharmacoEconomics – Open [1] explores RSAs in the EU from 2000–2015. It shows that during this period there was increased interest in, and uptake of, RSAs and discusses the reasons for this increase.

Risk sharing agreements to facilitate universal access to medicines

In the EU, near universal healthcare coverage is the norm and budgets are limited. To ensure universal access to new, innovative and effective drugs at an acceptable and manageable cost, innovative approaches to pricing and reimbursement of drugs are needed. Pharmaceutical manufacturers are increasingly expected to demonstrate the real-world value for money of their products. Their attempts to demonstrate value are often assessed by HTA agencies, but generally, there are limited data available on products at the time of launch. This means that HTA decisions can be slow, meaning manufacturers can lose out financially and/or payers are left only able to access more expensive and less effective medicines. To address this problem, at the time of launch when the value of a new or innovative medicine is not fully understood, national healthcare payers, HTA agencies and the pharmaceutical industry, have formal agreements by which they share the financial risk associated with the medicine’s launch and introduction. These are called managed entry agreements (MEAs); which are most commonly referred to as RSAs.

An extensive literature review the history of RSAs in the EU

Over the last 15 years (2000 to 2015), an increase in RSAs has been reported. By carrying out a systematic literature review, researchers at the University of Copenhagen in Denmark and Ghent University in Belgium have identified the underlying trends in RSAs that took place in the EU during this time. To do this review, Trevor Piatkiewicz of the University of Copenhagen and first author of the paper, looked at ‘grey literature’ from Google, Google Scholar, and the official websites of international organizations such as the World Health Organization (WHO), the International Society for Pharmacoeconomics and Outcomes Research (ISPOR), and the Organization for Economic Cooperation and Development (OECD) to create a list of keywords that could be used to identify relevant peer-reviewed articles. Once the keywords had been defined, Piatkiewicz used them to identify peer-reviewed articles about RSAs published between 2000–2015 by searching some commonly used databases (PubMed, Scopus, Web of Science and Embase). All articles that were included in this review were published in English and were conducted or published in and/or about EU Member States. In addition, only agreements or schemes relating to pharmaceutical products and/or involving the sale of pharmaceutical products were included, and only if the title of the article included or alluded to at least one of the keywords selected to indicate the content of the article was relevant to the objective of the review. There were also a number of exclusion criteria that are laid out in detail in the paper.

Potentially relevant articles found in the literature search were then divided into two groups, ‘quantitative articles’ which were used to explore changes in the level of interest in RSAs, and ‘qualitative articles’ which were used to explore the underlying reasons for the changes.

The literature screening enabled data from 238 scientific articles published between 2000 and 2015 to be extracted. Of these, 100 were said to contain quantitative data of interest and 138 qualitative data of interest. Overall, the literature search and evaluation showed that there has been a rise in the number of publications related to RSAs during this period. Piatkiewicz and co-authors Marie Traulsen and Tove Holm-Larsen, found that the increase in the number of publications related to RSAs was particularly significant between 2014–2015, which they attribute to an overall increased interest in, and knowledge of, RSAs.

Four key factors which influenced RSAs over time

A qualitative analysis of the articles was used to identify information about possible underlying reasons for the fluctuations in the yearly number of articles published between 2000–2015. Four overall themes emerged that appeared to influence interest in RSAs over time. These are summarized as follows:

1. 2000–2007: A push for value-based pricing (VBP)
During the early 2000s, across Europe there were increasing demands for VBP made by national healthcare payers. Publications on the subject during this time generally reflected VBP policies discussed by the UK and many articles questioned the necessity of such schemes.

2. 2007–2009: The economic crisis and a greater push to contain costs
Following the economic crisis of 2007–2008, healthcare resources came under increased stress and across Europe budgets were cut. Healthcare providers and HTAs became more concerned with cost-effectiveness and the budget impact of product approvals. Pharmaceutical companies experienced increase pressure to ensure the value of new drug products. Many countries implemented cost-containment strategies to reduce the price of new pharmaceuticals. The economic crisis during this time period pushed VBP implementation and ended the era of free pharmaceutical pricing in Europe. In addition, HTAs started to play an ever more important role as intermediaries between healthcare providers and pharmaceutical companies. These actions prompted an increase in reporting and discussion of VBPs, as has been reflected in an increase in publications during this period.

3. 2009–2011: General discussion about RSAs
From 2009–2010, there was a spike in the number of qualitative articles discussing the pros and cons of European RSAs. Schemes that had been introduced in preceding years were analysed, discussed and criticized. With the increased level of interest in RSAs, came valid arguments and questions surrounding their use. This resulted in a steady increase in the overall number of publications on performance-based schemes.

4. 2011–2015: RSAs diversified to be fit for purpose
Between 2011–2015 a steady increased interest in, and discussion of, RSAs was maintained. This is reflected by the increasing number of publications discussing RSAs during this time. Many existing schemes were adapted and developed across Europe and were made fit for purpose. Many studies noted there is no ‘one size fits all’ approach to RSAs that can be adopted, and each situation should be addressed individually, from both a country and product perspective. The total number of schemes reported plateaued between 2011–2013. Many existing schemes were adapted during this period, rather than new ones being created.

Overall, the review identified several countries that have had a major influence on RSA development and uptake between 2000–2015. These include France, Germany, Italy and the UK, although Eastern European nations began to play an increasing role in the latter years. Each country within the EU has adopted different strategies and developed different relationships with HTAs, which have led to noticeable differences in drug benefit evaluations, recommendations, and overall access to EU markets.

The uncertain future of RSAs

The review showed that increased reporting on pricing and reimbursement practices across the EU has led to an improved understanding of RSAs and that RSAs have evolved dramatically since their first conception and implementation. The report concludes by stating that RSAs may play an increasingly important role in the future of drug availability, particularly when it comes to high-priced personalized medicine options. However, the authors point out that pharmaceutical companies could negate the necessity for RSAs if they become better at creating and gathering the data necessary to allow them to build stronger approval arguments for their new drug products. Such data are needed to lower the risks of being rejected by HTA agencies. If successful, RSA conception, uptake and evolution will have played an important role in helping to reduce the financial burden on EU healthcare systems and allowing patients increased access to new, innovative and effective drugs.

Competing interests: None.

Provenance and peer review: Article abstracted based on published scientific or research papers recommended by members of the Editorial Board; internally peer reviewed.

Alice Rolandini Jensen, MSci, GaBI Journal Editor

Reference
1. Piatkiewicz TJ, Traulsen JM, Holm-Larsen T. Risk-sharing agreements in the EU: a systematic review of major trends. Pharmacoecon Open. 2018;2(2):109-23.

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2018 Pro Pharma Communications International

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.

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Submitted: 6 May 2018; Revised: 7 May 2018; Accepted: 8 May 2018; Published online first: 18 May 2018

Data and market exclusivity for originator medicines in the European Union (EU) create a barrier to market entry for generic medicines. Legislation means that generics cannot reach the market for at least 10 years following the originator marketing authorization. There are no exceptions to this rule which is a cause for concern for many EU Member States. Even high-income countries struggle to afford high-cost medicines under patent to the detriment of patients and overall health care. A recent study published in the Journal of Pharmaceutical Policy and Practice, looks at the current state of EU pharmaceuticals legislation and creates a proposal for greater coherence in this legislation [1].

Regulation concerning the marketing authorization of a generic medicine in the EU currently prohibits the use of the originator’s preclinical and clinical test data for an eight-year period. This is data exclusivity. Following this, market exclusivity means that a generic medicine in the EU cannot then reach the market until 10 years after the originator marketing authorization has passed. In some cases, an additional one year of market exclusivity can also be granted. There are no exceptions made to this rule, which is also known as the 8+2+1 rule.

Current EU medicines legislation goes beyond the requirements of the World Trade Organization (WTO) Trade-Related Aspects of Intellectual Property Rights (TRIPS) Agreement Art. 39.3. The TRIPS Agreement was set up to protect undisclosed test data in registration submissions of new chemical entities against unfair commercial use. However, it does not require countries to grant originator companies exclusive rights over data related to marketing approval. The legislation in place in the EU does grant such exclusive rights, creating an obstacle to the effective use of compulsory licensing.

As part of the WTO TRIPS Agreement, governments can allow third parties or themselves, the right to use a patent without the patent holder’s permission. Such TRIPS flexibilities were clarified in the 2001 WTO Doha Declaration on the TRIPS Agreement and Public Health. This has since resulted in low- and middle-income countries making use of these flexibilities to enable the supply of low-cost generic medicines for the treatment of HIV (human immunodeficiency virus). These flexibilities have a lot of potential which is being taken note of by many WTO countries. Since 2001, the UN High Level Panel on Access to Medicines has recommended their use and that legislation be implemented to enable compulsory licences to be issued that are ‘designed to effectuate quick, fair, predictable and implementable compulsory licenses for legitimate public health needs’.

The EU is yet to make use of TRIPS flexibilities. However, many European health services are currently being restricted by the high price of patented medicines. This results in reduced or denied access to certain medicines in many Member States. There have been requests for governments to address patent barriers made by many higher-income EU Member States.

In the EU, it is possible for individual nations to issue a compulsory licence to overcome patents. However, the regulatory requirements for marketing authorization within the EU, that include data exclusivity, are a matter of European pharmaceutical legislation. These systems together, lack coherence. This has led to cases such as that which occurred in Romania in 2016. Here, the Romanian Government considered issuing a compulsory licence for sofosbuvir, which is used to treat hepatitis C. However, in accordance with EU legislation, it is not possible to register a generic version of this medicine until 2022 due to data exclusivity, meaning that a compulsory licence could not be issued.

Some voluntary licences include a data exclusivity waiver to ensure effective availability of generic medicines. Such waivers are also provided in some middle- and high-income countries that are members of the WTO. These hope to aid generic medicines registration and sales when required to protect public health. They are explicit medicines regulations data exclusivity waivers or relate to the use of compulsory licences in the patent laws of different countries. Data exclusivity waivers are in existence in some non-EU countries including Chile, Colombia, Guatemala and Malaysia and should be considered in the EU.

In the US, data and marketing exclusivity rules are similar to those in the EU. Small molecule generics have a marketing exclusivity period of five years and this is 12 years for biologicals, with a data exclusivity period for the first four. In 2007, the US New Trade Policy authorized a public health exception to data/market exclusivity in the event of a compulsory licence or other requirements of public health. This allows countries that have signed US developing-country free-trade agreements to disregard data/marketing exclusivity as long as they take measures to protect public health. This can occur even in circumstances where a compulsory licence should be issued, however, its implementation does depend on the status of the patent of the medicine being considered.

In the EU, data and market exclusivity waivers do exist in accordance with the ‘EU regulation on compulsory licensing of patents for the manufacture of pharmaceutical products for export to countries with public health problems outside the EU’. Some EU trade agreements include provisions that can enable exceptions to exclusivity for reasons of public interest or under situations of national emergency or extreme urgency. Under these circumstances, third parties can be allowed access to certain data. Such an agreement exists between the EU and Peru.

Overall, despite the right that EU governments have to grant compulsory licences, there is a lack of legal coherence within the EU which prevents generic medicines being able to enter the market early. This is primarily due to data exclusivity and a lack of data exclusivity waivers. EU governments should attach conditions to licensing that enable the use of waivers within the EU and EU legislation needs to be amended to facilitate this. Such waivers do exist for pharmaceutical products exported from the EU. The burden on health budgets across the EU is considerable and EU law needs to act to ensure that there is easy access to new essential medicines to protect and promote public health.

Competing interests: None.

Provenance and peer review: Article abstracted based on published scientific or research papers recommended by members of the Editorial Board; internally peer reviewed.

Alice Rolandini Jensen, MSci, GaBI Journal Editor

References
1. ‘t Hoen EFM, Boulet P, Baker BK. Data exclusivity exceptions and compulsory licensing to promote generic medicines in the European Union: A proposal for greater coherence in European pharmaceutical legislation. J Pharm Policy Pract. 2017;10:19.

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2018 Pro Pharma Communications International

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.

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Submitted: 29 December 2017; Revised: 5 January 2018; Accepted: 12 January 2018; Published online first: 19 January 2018

A recent comparison of generic drug markets [1] explores the history of generics substitution and bioequivalence policies in the US, in order to understand the barriers to implementing reform of generic drug policies.

The history of generics substitution

In this case study, the authors investigated the barriers to generic drug policy reform, focusing on the history of both generics substitution and bioequivalence policies in the US.

The history of generic drug substitution in the US reveals consistent political conflicts, vested interests and lobbying by stakeholders with economic interests.

Since the beginning of generic drug substitution in the US, groups representing brand-name drug manufacturers have worked to prevent policy reform. In the 1940s, the National Pharmaceutical Council began lobbying against substitution, claiming that it would suppress innovation and reduce quality, soon joined by the American Medical Association (AMA) and the American Pharmacists Association. As a result of their activity, 44 states had banned generic drug substitution by 1959.

In the decades that followed however, support for generics substitution grew among pharmacists, boosted by the government’s efforts to find ways to cut spending in health care.

In 1981, the state of Oregon passed the first therapeutic substitution law and by the mid-1980s all 50 states had legalized the practice of generic drug substitution. In the years between 1987 and 1993, the number of organizations that allowed generics substitution (not including hospital pharmacies) doubled – reaching 70%.

Yet, substitution was not always mandatory and some states restricted it by allowing patients to refuse generics or only allowing certain drugs to be substituted. Even today, doctors in the US can easily block substitution by ticking the ‘dispense as written’ box on the prescription. There is no minimum standard of substitution, but in 2015 almost 90% of all prescriptions were filled with a generic drug.

Regulation of bioequivalence

Closely linked to changing substitution policies are changes in the regulation of bioequivalence. When regulators first began to call for generics substitution, there was no effective way to prove that generics would have the same medicinal effect as patented drugs. In fact, in 1967 it was found that generic versions of a popular antibiotic had a resistant coating that prevented the active ingredient from being released, causing a public scandal.

This was extremely damaging to the public perception of generics, but led the US Food and Drug Administration (FDA) to commission five external committees to investigate how to assess the bioequivalence of generic drugs. In 1984, FDA decided on a set of bioequivalence standards, commonly known as the Hatch-Waxman Act.

The authors say the issues of substitution and bioequivalence regulation in the US can help policymakers to avoid repeating similar mistakes and identify opportunities for reform.

What are the chances for reform?

High drug prices in the US are a persistent issue, and the rising cost of generic drugs and a lack of competition in the generic drug market in particular has gained public attention in recent years.

A 2016 poll found that the vast majority of people in the US are in favour of government action to cut prescription drug prices, and indeed the US Government has taken an increasing interest in drug prices. Several senators are investigating means of improving competition in the generic drug market, and some even suggest that the government should be able to block price increases on generic drugs.

President Donald Trump has supported calls to give the government more power to negotiate drug prices and to allow states to import cheaper drugs from other countries. He has also called for streamlining of the FDA drug approval process.

FDA Commissioner Dr Scott Gottlieb has also criticized delays to generic drug approvals and has recently taken steps to increase generic drug competition. However, there are concerns that changes to FDA processes might hamper their ability to check the effectiveness and safety of drugs. The authors also say it remains to be seen how these ideas will develop, given the uncertainty in current US health policy.

Chances for reform have in particular been hampered by recently proposed changes to the Affordable Care Act. In May 2017, a bill was passed to repeal and replace the Affordable Care Act, which would drastically change health care in the US, with huge implications for those on a low income. Although a Congressional Budget Office report estimated that this would save the government US$100 billion in just 10 years, the impact for the generic drug market was unclear.

Although the bill was defeated in July 2017, other forces are preventing intervention in generics policy. For example, AMA and the Pharmaceutical Research and Manufacturers of America (two major lobbying organizations) continue to oppose any government intervention in the generic drug market. Although they initially supported the Affordable Care Act, the authors suggest they only did so after being assured that there would be no price controls on medicines and no importation of cheaper medicines.

A more detailed discussion of this study, including investigations of European generic drug markets, has been presented in a previous paper [2].

Competing interests: None.

Provenance and peer review: Article abstracted based on published scientific or research papers recommended by members of the Editorial Board; internally peer reviewed.

Eleanor Bird, BSc (Hons), GaBI Journal Editor

References
1. Wouters OJ, Kanavos PG, McKee M. Comparing generic drug markets in Europe and the United States: prices, volumes, and spending. Milbank Q. 2017;95(3):554-601.
2. Delahunty M. A comparison of European and US generic drug markets. Generics and Biosimilars Initiative Journal (GaBI Journal). 2017;6(4):190-2. doi:10.5639/gabij.2017.0604.043

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2018 Pro Pharma Communications International

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.

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Submitted: 17 November 2017; Revised: 20 November 2017; Accepted: 22 November 2017; Published online first: 5 December 2017

The tumour necrosis factor (TNF) inhibitor infliximab is known to significantly improve the treatment of inflammatory autoimmune diseases such as Crohn’s disease, ulcerative colitis and rheumatoid arthritis. The high cost of biological originators, however, has meant that access to treatment has been determined by the ability to pay [1, 2]. The advent of lower-priced biosimilars could widen access to important therapies worldwide.

For the first time, questions surrounding the efficacy, safety and immunogenicity of switching from this originator to its biosimilar have been addressed by a randomized clinical trial comparing the TNF inhibitor infliximab with the less expensive biosimilar CT-P13. The NOR-SWITCH study [3] enrolled 482 patients with either Crohn’s disease (32%), ulcerative colitis (19%), spondyloarthritis (19%), rheumatoid arthritis (16%), psoriatic arthritis (6%) or chronic plaque psoriasis (7%). NOR-SWITCH, was a randomized, double-blind, parallel-group, non-inferiority comparative phase IV study, carried out over 52 weeks at 25 hospitals in Norway.

The study, published in May 2017, followed recommendation from the Norwegian Health Authorities. In 2014, CT-P13 was recommended by Norwegian Health Authorities for patients starting treatment with infliximab. Moving to the biosimilar cut the health authorities’ TNF inhibitor spending by 39% in the first year, increasing to 69% after a tender the following year. Such savings, if replicated in other countries, could improve overall and earlier access to TNF inhibitors worldwide.

Starting patients on CT-P13 therapy is widespread, but switching stable patients who are already on infliximab to the biosimilar is controversial. Until now there have been no randomized studies to monitor the safety and efficacy of such a switch.

Data from earlier studies, and from extensions of the PLANETRA and PLANETAS studies (which looked at the comparability of infliximab and CT-P13 in patients with rheumatoid arthritis and ankylosing spondylitis, respectively) [4], had not raised any major concerns about the efficacy or safety of CT-P13. However, to the authors’ knowledge, NOR-SWITCH is the first randomized clinical trial to show that switching from an originator to a biosimilar TNF inhibitor is not inferior to continued treatment with the originator drug.

The primary endpoint of the study was disease worsening during follow-up according to either worsening in disease-specific measures (according to accepted scoring systems for each of the six diseases studied) or agreement between the patient and investigator that the disease was worsening. Secondary endpoints included time to disease worsening, study drug discontinuation, overall remission status based on the disease-specific measures, and changes (follow-up minus baseline) in investigator and patient global assessments.

Reports of adverse events or serious adverse events during the trial were not different between patients treated with CT-P13 and patients treated with infliximab. There were no deaths or suspected unexpected serious adverse reactions. More patients in the infliximab originator group, than in the CT-P13 group, had infusion-related reactions and discontinued the study. As in the extensions to PLANETRA and PLANETAS, no differences in immunogenicity were detected between the treatment groups.

The NOR-SWITCH trial failed to find inferiority switching from infliximab originator to CT-P13 according to a pre-specified non-inferiority margin of 15%. The choice of margin was not straightforward – too narrow and the trial would have been infeasible; too wide and clinically important differences would be missed. The 15% margin was based on the PLANETRA trial and on discussions with the Norwegian Medicines Agency. The European Medicines Agency also chose a 15% margin for their assessment report of CT-P13, but the US Food and Drug Administration has suggested a 12% margin for such studies.

NOR-SWITCH focussed on the important and controversial issue of switching from originator to biosimilar infliximab in stable patients. It was the first entirely government-funded randomized study to do this. The Norwegian Government granted NOK 20 million (Euros 2.2 million) in the 2014 governmental budget for the study.

The results of the study suggest that patients can safely be switched between originator and biosimilar infliximab. The authors warn that it is possible that the 15% margin might have been too wide to exclude all clinically important differences in individual diseases. Caution is needed before generalizing these findings to other biological agents, and further studies are needed to look at the safety and efficacy of multiple switching between originator and biosimilar.

There is a 6-month extension study ongoing, which will compare patients who received CT-P13 during the year-long NOR-SWITCH trial with patients switching to CT-P13 having been treated with the infliximab originator.

The authors predict that we are only at the very beginning of the biosimilar era and that switching between an ever-growing number of biosimilar medicines will become more prevalent. Studies that focus on multiple switches (from one biosimilar to another, and from a biosimilar back to the originator product) will be needed.

Competing interests: None.

Provenance and peer review: Article abstracted based on published scientific or research papers recommended by members of the Editorial Board; internally peer reviewed.

Bea Perks, PhD, GaBI Journal Editor

References
1. Vogler S, Schneider P. Do pricing and usage-enhancing policies differ between biosimilars and generics? Findings from an international survey. Generics and Biosimilars Initiative Journal (GaBI Journal). 2017;6(2):79-88. doi:10.5639/gabij.2017.0602.015
2. Putrik P, Ramiro S, Kvien TK, Sokka T, Pavlova M, Uhlig T, Boonen A; Working Group ‘Equity in access to treatment of rheumatoid arthritis in Europe’. Inequities in access to biologic and synthetic DMARDs across 46 European countries. Ann Rheum Dis. 2014;73(1):198-206.
3. Jørgensen KK, Olsen IC, Goll GL, Lorentzen M, Bolstad N, Haavardsholm EA, et al. NOR-SWITCH study group. Switching from originator infliximab to biosimilar CT-P13 compared with maintained treatment with originator infliximab (NOR-SWITCH): a 52-week, randomised, double-blind, non-inferiority trial. Lancet. 2017;389(10086):2304-16.
4. Switching from the infliximab reference product to CT-P13 in patients with rheumatoid arthritis or ankylosing spondylitis: results of the PLANETAS and PLANETRA extension studies. Generics and Biosimilars Initiative Journal (GaBI Journal). 2016;5(2):94-5. doi:10.5639/gabij.2016.0502.023

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2018 Pro Pharma Communications International

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.

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Submitted: 19 June 2017; Revised: 5 September 2017; Accepted: 6 September 2017; Published online first: 19 September 2017

Introduction

Comparative research on the European and US generic drug markets based on 2013 IMS data across 13 European countries with different generic drug policies has recently been accepted for publication in the Milbank Quarterly [1], and abstracted here from a pre-print of the accepted article published on LSE Research Online [2].

In a price-index analysis, generic drug prices and market shares of 200 active ingredients were compared across 13 European countries to establish the extent of variation between them. The selected countries were Belgium, Denmark, France, Germany, Greece, Italy, The Netherlands, Poland, Portugal, Spain, Sweden, Switzerland and the UK.

Recently published peer-reviewed studies, academic books and grey literature published since 2000 were reviewed for additional information on prices and use of generic drugs in Europe and the US. Published data on existing generic drug policies, and measures to increase generic drug use and to stimulate price competition, were also reviewed.

Methods

The investigators used Laspeyres indexes to compare drug prices for the 200 active ingredients selected. These are price ratios used to monitor change in price levels over time.

The first step was to calculate the average price per dose (total sales across form-strength combinations divided by number of doses sold). Both ex-manufacturer and retail prices of each active ingredient were calculated.

A subset of 80 active ingredients prescribed in all 13 countries were then identified and comparative statistics generated, e.g. proportion of generic drug spend accounted for by the sample and generic drug market share.

The Laspeyres indexes were calculated using weights from a base country. In this case, Germany was selected, as it is the largest drug market in Europe by revenue. The base country was assigned a base value of 100. The authors give an example of a country with a price value of 140 and explain that it would have 40% higher prices than Germany, and a country with a price value of 60 would have prices 40% lower than Germany.

Findings

Price index
The price-index analyses showed that prices and market shares varied widely across Europe. Swiss ex-manufacturer prices, for example, were more than 2.5 times those in Germany, and more than six times those in the UK.

The gap, however, was smaller for retail prices, which include distribution costs and markups charged by wholesalers and pharmacies. Belgium, Portugal and Spain had lower retail prices but higher ex-manufacturer prices than Germany.

The proportion of prescriptions filled with generics (generic drug market share) was low (< 40%) in Switzerland (17%), Italy (19%), Greece (20%), France (30%), Belgium (32%) and Portugal (39%); moderate (between 40% and 60%) in Sweden (44%), Spain (47%), Denmark (54%) and Poland (57%); and high (< 60%) in The Netherlands (70%), Germany (80%) and the UK (83%).

The authors acknowledge a number of limitations to their price comparisons. Generic drugs sold in hospital pharmacies, biosimilar products, off-patent originator drugs, and parallel-traded generics were excluded. Retail data were unavailable for The Netherlands and the UK.

The Laspeyres index also assumes that demand for prescription generic drugs is price inelastic, i.e. change in the price of a generic drug does not affect demand. The authors also acknowledge that IMS Health data do not reflect confidential rebates and discounts; therefore, the list prices, i.e. official prices before discounts, may overestimate the actual prices paid for some products.

Generic drug use in Europe and the US
The additional review of published data undertaken by Wouters et al. shows that cost savings can be made in off-patent drug markets in Europe and the US.

For example, a report by the European Commission (EC) [3] found that the average time taken for a generic drug to reach market from the time a brand-name drug loses its exclusivity was seven months, estimating the cost to EU payers to be US$3 billion a year based on retail prices. After two years, generic drug penetration accounted for less than half of EU sales. The report also found that price reductions took longer in Europe, and that EU countries had different pricing and reimbursement regulations, prescribing policies and generic substitution laws.

Wouters et al. also cite a report published by the Organisation for Economic Co-operation and Development (OECD) [4] showing that in 2013, 84% of drug prescriptions in the US were for generic drugs, following the US trend of low generic drug prices and high volume use [5].

They also found research demonstrating decreased competition in the US generics sector. In a study by Schondelmeyer et al. for the AARP Public Policy Institute [6], a slower rate of decline (4%) of the total cost of 280 widely used generic drugs was reported between 2012 and 2013 compared with the previous seven years. This was attributed mainly to supply-chain disruptions, market conditions forcing firms out of business, mergers and acquisitions, and delays in processing generic drug applications by the US Food and Drug Administration (FDA) [6].

According to Greene et al. [7] reduced competition has enabled some pharmaceutical companies to drive up the prices of generic drugs. The US Government Accountability Office reported ‘extraordinary’ price increases of 100% or more for 315 out of 1,441 generics studied [8].

Wouters et al. found a range of reports on other factors affecting utilization rates and the adoption and effectiveness of policies, including the perception by US and European physicians, pharmacists and patients that generic drugs are not bioequivalent; different regulatory structures; lobbying powers of special-interest groups; patent litigation systems; and political economies of healthcare systems.

Published data on drug policies in Europe and the US were also reviewed to identify best practice. Although many European countries share common policies, they found that the method of implementation varied widely, and pricing, prescribing, and substitution policies can affect prices and usage of generics.

The authors establish that generics substitution in Europe is mandatory in 13 countries, voluntary in 14 and forbidden in five. In the US, where generics prescribing is universally voluntary, substitution laws differ between states.

In researching internal reference pricing and tendering, the authors found that most European countries used internal reference pricing and, in some, health insurers use a tendering process to obtain generic drugs in bulk from manufacturers offering the best prices. In the US, internal reference pricing and tendering is not used for generic drugs sold in non-hospital pharmacies.

The authors have produced useful maps to show the distribution of internal reference pricing, generics prescribing, generics substitution and tendering in the EU and four European Free Trade Association countries, and laws governing drug substitution in the US, respectively.

Another report by the EC [9] showed that, with the exception of Denmark, Germany and the UK, price controls are imposed on generics, i.e. maximum allowable prices, and are often linked to the prices of brand-name drugs. The authors also identify a World Health Organization report [10] that highlights the extent to which EU governments block price increases in the interests of public health and spending. The US Government, however, does not impose price controls on generics.

Measures taken to increase generic drug use and stimulate price competition
On the basis of available evidence from Europe and the US, Wouters et al. identify measures that are effective in promoting price competition among pharmaceutical companies and increasing the use of generic drugs.

The authors believe that one important measure is to streamline the generic drug approval process to facilitate market entry. They highlight work by Kesselheim et al. [5, 11], who found that regulators tend to prioritize applications from manufacturers attempting to bring to market a generic medicine sold by three or fewer firms, thereby exerting downward pressure on prices and ensuring that individual companies have less influence over prices. For off-patent drugs facing limited or no competition, Kesselheim et al. [5] suggest that FDA import new generic drugs temporarily from countries such as Canada and EU Member States, with high regulatory standards to avoid paying high premiums.

For those countries experiencing a backlog of applications for generic drug approval, the authors again refer to Kesselheim et al. [5] who suggest that resources could be allocated to national regulators to speed up the review process or a fee could be charged to generic drug firms, as in the US, to increase resources available for the drug approval process.

Wouters et al. highlight new US legislation proposed in 2015 to make it easier for drug companies to challenge patents without enduring lengthy and costly litigation [12]. The bill is still under consideration, and the EC has called for similar measures.

According to research published by the US Federal Trade Commission [13], a ban on pay-for-delay deals by regulators could save US$3.5 billion a year. Wouters et al. discuss how these deals involve brand-name pharmaceutical companies offering generics manufacturers cash to delay bringing their generic drug to market, thereby ensuring that brand company monopoly is retained and higher prices can be charged to consumers.

They also discuss how regulators could facilitate access to samples of brand-name products; since 2007, a legal loophole in the US has prevented generics companies accessing samples for the purpose of conducting bioequivalence testing before patent expiry [14, 15].

In countries such as Denmark, Sweden, the UK and the US, price competition is encouraged, and Wouters et al. identify studies showing that, where generic drug companies are permitted to set their own prices, and physicians and pharmacists are incentivized to prescribe and dispense the least expensive generics, over time prices are effectively reduced. Tendering has also been shown to lower administrative costs, reduce the price of generics and improve price transparency.

The authors believe that countries should require pharmacists to substitute generic drugs for brand-name drugs based on a report by the EC [16] showing that such policies result in generic drugs entering the market more quickly and having more immediate take up.

One study by Shrank et al. [17] showed that blocking the use of generic drugs costs the US US$7.5 billion a year, including US$1.2 billion in out-of-pocket fees for patients. Wouters et al. argue that generic drugs should be encouraged or even required, unless there are legitimate reasons to prescribe a brand-name drug over a generic equivalent.

They also review research on academic detailing, showing that the practice of using trained, impartial experts to provide unbiased information to clinicians about the effectiveness, safety and costs of drugs, improves compliance with desired prescribing practices [18].

The authors found published research on the positive effect of financial incentives in improving rates of generics prescribing, but evidence for this effect was limited.

In some countries, regulators permit pharmacists to substitute a generic drug for a brand-name drug with a different active ingredient if both drugs belong to the same therapeutic class and have the same indication. Wouters et al. cite a report by Johansen et al. [19] who estimate that an extra US$73 billion per year is spent in the US (about 10% of total drug spending) on brand-name drugs with available therapeutic substitutes.

Therapeutic substitution, however, is not as straight forward to implement, and Wouters et al. suggest that the relevant authorities and clinical organizations should develop appropriate protocols and strengthen coordination between physicians, pharmacists and insurers to encourage its wider practice [19–20].

The authors conclude their policy evaluation with a discussion of the obstacles preventing generic drug policies, using a historical case study example from the US to help explain why similar initiatives previously failed. This part of the discussion will be abstracted in a future edition of GaBI Journal.

Competing interests: None.

Provenance and peer review: Article abstracted based on published scientific or research papers recommended by members of the Editorial Board; internally peer reviewed.

Maysoon Delahunty, BA, GaBI Journal Editor

Reference
1. Wouters OJ, Kanavos Panos G, McKee M. Comparing generic drug markets in Europe and the United States: prices, volumes, and spending. Milbank Q. 2017;95(3):554-601.
2. Wouters OJ, Kanavos Panos G, McKee M. Comparing generic drug markets in Europe and the U.S.: prices, volumes, and spending. LSE Research Online.
3. European Commission. Pharmaceutical sector inquiry – final report. 8 July 2009 [homepage on the Internet]. [cited 2017 Sep 5]. Available from: http://ec.europa.eu/competition/sectors/pharmaceuticals/inquiry/staff_working_paper_part1.pdf
4. Organisation for Economic Co-operation and Development. OECD Health Statistics 2016 [homepage on the Internet]. [cited 2017 Sep 5]. Available from: https://www.oecd.org/els/health-systems/Table-of-Content-Metadata-OECD-Health-Statistics-2016.pdf
5. Kesselheim AS, Avorn J, Sarpatwari A. The high cost of prescription drugs in the United States: origins and prospects for reform. JAMA. 2016;316(8):858-71.
6. Schondelmeyer SW, Purvis L. Trends in retail prices of generic prescription drugs widely used by older Americans, 2006 to 2013. Washington, D.C.: AARP Public Policy Institute, 2015.
7. Greene JA, Anderson G, Sharfstein JM. Role of the FDA in affordability of off-patent pharmaceuticals. JAMA. 2016;315(5):461-2.
8. United States Government Accountability Office. Generic drugs under medicare: part D generic drug prices declined overall, but some had extraordinary price increases.Washington, D.C.: GAO, 2016 [homepage on the Internet]. [cited 2017 Sep 5]. Available from: http://www.gao.gov/assets/680/679022.pdf
9. European Commission. Generic policies in the European Union and EEA-EFTA countries in 2009. Brussels, Belgium: DG Enterprise, 2009.
10. Panteli D, Arickx F, Cleemput I, et al. Pharmaceutical regulation in 15 European countries: review. Health Systems in Transition, 18(5). pp. 1-118. ISSN 1817-6127.
11. Engelberg A, Avorn J, Kesselheim A. Addressing generic drug unaffordability and shortages by globalizing the market for old drugs. Health Policy Lab: Health Affairs; 2016.
12. Treasure CL, Kesselheim AS. How patent troll legislation can increase timely access to generic drugs. JAMA Intern Med. 2016;176(6):729-30.
13. Federal Trade Commission. Pay-for-delay: how drug company pay-offs cost consumers billions [homepage on the Internet]. [cited 2017 Sep 5]. Available from: https://www.ftc.gov/sites/default/files/documents/reports/pay-delay-how-drug-company-pay-offs-cost-consumers-billions-federal-trade-commission-staff-study/100112payfordelayrpt.pdf
14. Sarpatwari A, Kesselheim A. Ensuring timely approval of generic drugs. Health Policy Lab: Health Affairs; 2015.
15. Sarpatwari A, Avorn J, Kesselheim AS. Using a drug-safety tool to prevent competition. N Engl J Med. 2014;370(16):1476-8.
16. Shrank WH, Liberman JN, Fischer MA, et al. The consequences of requesting “dispense as written”. Am J Med. 2011;124(4):309-17.
17. O’Brien MA, Rogers S, Jamtvedt G, et al. Educational outreach visits: effects on professional practice and health care outcomes. Cochrane Database Syst Rev. 2007;(4):CD000409.
18. Johansen ME, Richardson C. Estimation of potential savings through therapeutic substitution. Jama Intern Med. 2016;176(6):769-75.
19. Ross JS. Therapeutic substitution-should it be systematic or automatic? JAMA Intern Med. 2016;176(6):776.
20. Greene JA. Generic: the unbranding of modern medicine. Baltimore: Johns Hopkins University Press; 2014.

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2018 Pro Pharma Communications International

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.

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Submitted: 13 September 2017; Revised: 17 September 2017; Accepted: 18 September 2017; Published online first: 25 September 2017

Both pharmacists and doctors in Guatemala lack trust in generic medicines, according to a study carried out by a local non-governmental organization (NGO) [1]. The authors make recommendations for increasing generics uptake, including changing dispensing practices and improving state regulation.

Low-cost generic medicines are key to increasing access to essential drugs in low- and middle-income countries (LMICs), including much of Latin America. As highlighted by a 2005 World Health Organization survey [2], there is a particular need for generic drug programmes in this part of the world. Generic drugs are becoming even more necessary as the burden of chronic diseases, such as cardiovascular disease, cancer and diabetes, increases in Latin American countries.

A recent study [1] focused on the use of generic drugs in Guatemala, the most populous country in Central America. Like many other Latin American countries, although Guatemala has a robust domestic manufacturing market, the vast majority (70%) of its drugs are imported (mostly from Mexico, its border country) and generic drug uptake is limited.

Among the factors limiting access to generics in Guatemala is intellectual property law, which offers significant protection for originator drugs and consequently delays market entry for generics. For example, a generic version of Sanofi’s long-acting insulin Lantus would still be restricted in Guatemala even after losing its patent in the US.

Furthermore, most generics sold in Guatemala are branded, i.e. sold under a trade name. These branded versions are aggressively marketed to consumers, allowing a premium to be charged and reducing market share for non-branded and cheaper generics.

Marketing strategies used by branded generics (and originator drugs) capitalize on consumer concern regarding the quality of generic drugs – another major factor impacting their use in Guatemala. One such advert for an originator diabetes medicine reads: ‘I have diabetes. If my medicine fails, I could suffer a diabetic coma. I don’t play around; I only use the real thing. Trusted brands have studies that back up their quality, efficacy and safety. Respect the medical prescription. Ask your doctor or your pharmacist for originator medicines.’

Quality concerns however are partly grounded in reality, as domestic generics manufacturers operate under out-of-date manufacturing laws and quality can be poor. Data from the International Medicines Quality Database, for example, showed that over 20% of samples submitted from Guatemala failed to pass a quality test. Further studies showed that several generic drugs made in Guatemala were not bioequivalent to their originators.

Finally, there is deep mistrust of the political system and its ability to properly monitor drug supply, exacerbated by a number of high-profile scandals in 2014. At the ground level, doctors – although legally required to include generic names in prescriptions – generally do not do so in practice.

Although there are data available on barriers to entry for generics in Guatemala, it is not clear how the attitudes of generics gatekeepers (physicians and pharmacy staff) impact their use. The authors of this paper therefore set out to explore perceptions among doctors and retail pharmacists on generic medicines, and how these perceptions influence prescribing behaviour.

The authors worked for the Maya Health Alliance, an NGO focused on treating chronic diseases among indigenous people in rural Guatemala. They interviewed 30 pharmacy staff and 12 doctors working in three towns in Guatemala that contain large numbers of patients with chronic diseases.

Retail pharmacy staff, defined as any pharmacy worker who dispenses medicines, were recruited through random sampling of pharmacies across five different categories (national pharmacy franchise; discount local pharmacy; non-discount local pharmacy; hybrid clinic-pharmacy; or government-subsidized pharmacy). Three pharmacies were randomly selected from each category in each of the three towns. Physicians were recruited using a different sampling method (convenience sampling), which involved contacting physicians in each town based on referrals from other healthcare professionals.

Semi-structured interviews lasting up to 45 minutes were used to understand perceptions of low-cost generic medicines and roles in choosing medicines among pharmacists and doctors. While interviews with pharmacy staff focused on training, perceptions of generic medicines and opinions about the roles of pharmacy staff and physicians in care, interviews with doctors also discussed prescribing practices. The data was subsequently analysed to identify the major themes, using a combination of descriptive and quantitative analysis methods.

Pharmacy staff and physicians were doubtful about both the safety and effectiveness of generics, in many cases considering their low cost as proof of their lower quality. Doctors were generally more likely than pharmacists to be wary of generics, with 55% stating that low-cost generics were not as safe or effective as branded drugs.

The researchers focused on perceptions of generics for two common chronic diseases: diabetes and high blood pressure (hypertension). For these diseases, the decision to use a generic version of a drug was based on several factors, including the patient’s income and preferences, but mainly doctor recommendations (as pharmacy staff generally defer to physician prescriptions). Prescribing practices among doctors varied widely and were heavily influenced by perceptions of generics, with one physician even stating: ‘To prescribe generics is to play with the life of the patient’.

Overall, the study shows that physician and pharmacist perceptions of generics have a big influence on their clinical use, especially when it comes to chronic diseases such as diabetes. To improve generic drug use in Guatemala, the authors say negative opinions of generics should be tackled. They further suggest laws requiring generic name in prescriptions should be enforced and communication between prescribers and pharmacists improved.

They also say state regulation and monitoring of drug supply should be improved, but note that this may be difficult to achieve in Guatemala’s current political climate. They therefore recommend commitments to increased transparency and accountability, for example, by reporting on compliance with international manufacturing standards. They finally suggest that self-regulation in the generics industry could improve quality and thus public perceptions.

Competing interests: None.

Provenance and peer review: Article abstracted based on published scientific or research papers recommended by members of the Editorial Board; internally peer reviewed.

Eleanor Bird, BSc (Hons), GaBI Journal Editor

References
1. Flood D, Mathieu I, Chary A, García P, Rohloff P. Perceptions and utilization of generic medicines in Guatemala: a mixed-methods study with physicians and pharmacy staff. BMC Health Serv Res. 2017;17(1):27.
2. World Bank. Health, Nutrition, and Population Family (HNP). Homedes N, López Linares R, Ugalde A. Generic drug policies in Latin America. March 2005 (homepage on the Internet]. [cited 2017 Sep 17 ]. Available from: http://apps.who.int/medicinedocs/documents/s16741e/s16741e.pdf

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2017 Pro Pharma Communications International

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.

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Submitted: 13 March 2017; Revised: 15 March 2017; Accepted: 16 March 2017; Published online first: 29 March 2017

Generic drug manufacturing of four major cancer drugs could massively reduce their costs to the National Health Service in the UK, according to a study published in the British Medical Journal [1]. The study shows that generics production and importation could reduce UK drug prices by over 99%. This article summarizes the major results of the research study.

The study estimated the lowest possible treatment costs for four cancer drugs.

Methods

Bortezomib (Velcade)
Bortezomib, marketed as Velcade by Takeda Oncology, is used to treat multiple myeloma and mantle cell lymphoma. The drug can extend life expectancy by an average of six months over standard treatment but costs are around GBP 18,000 per patient. It was recommended against by the UK National Institute for Health and Care Excellence (NICE) in October 2006 due to cost issues.

Bortezomib Accord, a generic of Velcade, has been authorized in the EU since April 2004. Studies have demonstrated satisfactory quality.

Dasatinib (Sprycel)
This anticancer drug, marketed by Bristol-Myers Squibb (BMS), is approved for use in leukaemia (chronic myelogenous leukaemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL)). It was also recommended against by NICE due to its high cost–benefit ratio.

There is not yet a generic version of this drug available in Europe. A recent decision by the European Patents Office means BMS will lose its patent protection on Dasatinib in the EU, which is currently set to expire by 2020.

Everolimus (Afinitor)
Everolimus is a derivative of the immunosuppressant rapamycin. It is marketed by Novartis and is used to treat kidney cancer and types of pancreatic cancer. It has also been deemed cost-ineffective by NICE and is included on the Cancer Drugs Fund (CDF) list. The CDF helps patients in England get access to drugs that are not available on the National Health Service (NHS), but has been criticized for rewarding ‘poor quality’ drugs.

There is currently no generic version of this drug available in Europe. This study found one generic, available in India.

Gefitinib (Iressa)
Marketed by AstraZeneca and Teva Pharmaceuticals, gefitinib inhibits the epidermal growth factor receptor, which is overactive in cancers such as non-small cell lung cancer. It is the only drug of the four considered cost-effective by NICE, and has been recommended by the institute as a treatment for people with the advanced form of non-small cell lung cancer.

There is no generic available in Europe. This study found one generic, available in India.

These four drugs were selected based on their clinical importance, the innovative nature of their pharmacological activity and the availability of data on their generic prices. The UK scientists calculated the target costs for each drug using a production cost algorithm, which used per-kilogram active pharmaceutical ingredient (API) prices and standard doses to calculate the estimated generic drugs price per patient per year. Where export data were not available, the authors calculated the target cost as the lowest available generic drug price. Prices for the drugs were identified in 11 countries, using national databases and online price comparison tools. They also considered patent expiry dates and total eligible treatment populations.

The researchers calculated generic drug price estimates for dasatinib and gefitinib, but due to a lack of export data, the lowest priced product globally was compared to UK prices for bortezomib and everolimus.

Results

Bortezomib (Velcade)
Based on a recommended dose of 1.3 mg/m² for a body surface area of 1.8 m² to be taken twice a week for two weeks, followed by a resting week, the authors calculated that the per-patient yearly API requirement for this drug is 159 mg. The lowest available generic price was GBP 199.92 per 3.5 mg vial, which was for an Indian generic. The patent expiry dates for this drug are 2014–2022.

Dasatinib (Sprycel)
Based on a recommended dose of 100 mg/day, the per-patient yearly API requirement for dasatinib is 36.5 g. Assuming this dosage, the estimated price for dasatinib was GBP 9.43 per month and GBP 122.95 per year. The lowest available price for the drug was from the originator company (BMS) in Brazil, at GBP 769.03 per month. The patent expiry dates for this drug are 2020–2026.

Everolimus (Afinitor)
A 10 mg daily dose of everolimus equates to a per-patient yearly API requirement of 3.7 g. For off-label use, the lowest available generic drug price was GBP 688.96. For on-label usage, the lowest available generic drug price globally was GBP 851.65. Both prices were for generics produced by Indian firms. The patent expiry dates for this drug are 2019–2025.

Gefitinib (Iressa)
Gefitinib’s recommended daily dose of 250 mg equals a per-patient yearly API requirement of 91.3 g. The estimated price was GBP 10.26 per month, and GBP 133.73 per year. The lowest available generic drug price was GBP 90.49 per month. The patent expiry date for this drug is 2017.

Finally, incidence data were used to estimate the eligible global and UK population. Gefitinib had the highest total numbers eligible for treatment per year at 291,393 (7,104 in the UK), followed by everolimus with 282,678 (9,780 UK), bortezomib with 143,385 (6,014 UK), and finally dasatinib with 52,280 (817 UK). The total global eligible treatment population was 769,736.

Overall, this study suggests that significant price reductions could be achieved for new cancer drugs in England. Target prices were GBP 411 per cycle for bortezomib, GBP 9 per month for dasatinib, GBP 852 per month for everolimus and GBP 10 per month for gefitinib. Compared to current list prices, these represent reductions of over 99%. Specifically, generic drug production could reduce the UK price of dasatinib by 99.6%, and the UK price of gefitinib by 99.5%. Importation of Indian generics for bortezomib and everolimus would represent price decreases of 74% and 71%, respectively.

Competing interests: None.

Provenance and peer review: Article abstracted based on published scientific or research papers recommended by members of the Editorial Board; internally peer reviewed.

Eleanor Bird, BSc (Hons), GaBI Journal Editor

Reference
1. Hill A, Redd C, Gotham D, Erbacher I, Meldrum J, Harada R. Estimated generic prices of cancer medicines deemed cost-ineffective in England: a cost estimation analysis. BMJ Open. 2017;7(1):e011965.

Disclosure of Conflict of Interest Statement is available upon request.

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