Table 5 Studies of TRIPS-plus rules

Data exclusivity

Kesselheim and Solomon 2010 [98]

Retrospective study to explore increases in the cost of old drug Colchicine arising from market exclusivity.

After the FDA approved Colcrys, the manufacturer brought a lawsuit seeking to remove any other versions of colchicine from the market and raised the price by a factor of more than 50, from $US0.09 per pill to $US4.85 per pill. Use of the new brand-name colchicine could add as much as $US50 million per year to insurance programs’ budgets. The implications of market exclusivity for public health can be substantial.

Nelson et al. 2011 [99]

Retrospective econometric modelling to estimate the cost impact of the 6-month exclusivity extension policy on the Utah Medicaid drug programme. Also projects the cost impact of this policy on Medicaid programmes in the US during the 18 months following patent expiration.

The 6-month extension policy was estimated to cost Utah’s Medicaid $US2.2 million for three drug classes over the 18 months following the original patent expiration date (year 2007 values). Projected to the US Medicaid population, this cost was $US430 million. For the individual drugs the percentage cost decrease in reimbursement amount resulting from exclusivity expiration and generic entry ranged from 24.4% for enalapril to 3.8% for pravastatin sodium.

Kesselheim et al. 2006 [100]

Retrospective econometric study to assess the cost of market-exclusivity extensions, artificially elevated generic prices, and slow adoption of generics when therapeutically equivalent generics could have been available sooner and at lower prices.

The delay in availability, elevated prices, and slow uptake of generic alternatives for amoxicillin/clavulanate, metformin, and omeprazole alone cost Medicaid $US1.5 billion in 2000–2004.

Patent term extensions

The Parliamentary Budget Officer 2018 [101]

Prospective modelling study to examine the fiscal cost to the Canadian federal government of patent extension.

The increase in expenditures nationally would have reached roughly $C392 million had the two-year certificates of supplementary protection been fully in place in 2015. For provincial public programs, the cost would have been $C214 million.

Di Matteo and Grootendorst 2002 [102]

Retrospective econometric modelling to estimate the socioeconomic and demographic determinants of real per capita provincial government drug expenditure in Canada over 1975-2000.

Any significant effects of the patent-term extensions of 1987 (Bill C-22) and 1993 (Bill C-91) on provincial drug expenditures occurred after 1995. The analysis suggests that either Bill C-91 had a more pronounced effect on drug expenditures than did Bill C-22, or the effect of the earlier legislation on drug expenditures operated with a lag, or the legislation had little effect on drug costs, and the post-1995 increase in drug expenditures is due to other factors, such as the introduction of new drugs that would have been introduced irrespective of Canada’s patent legislation

Harris et al. 2013 [103]

Retrospective econometric study to examine the Australian provisions for extending the terms of eligible pharmaceutical patents to determine their effectiveness in securing timely access to competitively priced pharmaceuticals and in supporting innovation and employment in the industry.

The estimate of cost of patent term extensions for 2012-13 is around $A 240 million in the medium term and, in 2012 dollars, around $A 480 million in the longer term. The Review finds that the increased patent protection afforded by increasing patent life has not led to an increase in investment in Australian pharmaceutical R&D that is commensurate with the cost to Australia.

Secondary patenting

Kapczynski et al. 2012 [104]

Retrospective study to examine the prevalence of secondary patents and their impact on patent life.

Independent formulation patents add an average of 6.5 years of patent life, independent method of use patents add 7.4 years, and independent patents on polymorphs, isomers, prodrug, ester, and/or salt claims add 6.3 years. There is evidence that late-filed independent secondary patents are more common for higher sales drugs.

Amin and Kesselheim 2012 [19]

Retrospective study to examine how secondary patents can extend market exclusivity and thus delay generic competition. Study based on two key antiretroviral drugs: ritonavir (Norvir) and lopinavir/ritonavir (Kaletra).

108 patents were identified, which together could delay generic competition until at least 2028—12 years after the expiration of the patents on the drugs’ base compounds and 39 years after the first patents on ritonavir were filed. Some of the secondary patents that were reviewed were found to be of questionable inventiveness.

Feldman 2018 [105]

Retrospective study to examine the proportion of Orange Book entries which indicate evergreening. Considers both patent and data exclusivity entries.

Rather than creating new medicines, pharmaceutical companies are largely recycling and repurposing old ones. Specifically, 78% of new Orange Book records were for existing drugs. Extending protection is particularly pronounced among blockbuster drugs. Once companies start down the road of extending protection, they show a tendency to do this multiple times. Increase over time in patents added. New data exclusivities focus on orphan drugs, new patient populations, new products and new uses.

Beall et al. 2019 [106]

Retrospective study to determine whether patents on medical devices effectively extend the monopoly period for pharmaceuticals and whether this constitutes evergreening.

Unexpired device patents exist for 90% of the 49 medicine/device product combinations studied and were the only sort of unexpired patent for 14 products. Overall, 55% of the 235 patents found were device patents. Comparing the last-to-expire device patent to the last-to-expire active ingredient patent, the median additional years of patent protection afforded by device patents was 4.7 years. Incremental, patentable innovation in devices to extend the overall patent protection of medicine/device product combinations is very common.

Yin 2015 [107]

Retrospective study to assesses the welfare gains from incremental innovation in pharmaceuticals.

Consumer surplus loss due to market exclusivity extensions far exceeds the consumer surplus benefits from incremental innovation. Market exclusivity granted for incremental innovations in SSRIs has resulted in a $US37 billion social welfare loss from 1996 to 2011. The result suggests that policy makers should reconsider the provisions for granting market exclusivity to incremental innovations.

Hao et al. 2015 [108]

Retrospective statistical analysis to assess trends in fixed dose combinations (FDCs) and single active ingredients approved by the FDA in the period 1980-2012. Focuses on consequent time lags and estimates the effective patent and exclusivity life of FDC drugs compared to the single active ingredients included in the combination.

FDC drugs which are not new molecules added a median of 9.70 years to the patent and exclusivity life of the single active ingredients in the combination. FDC drug approvals significantly increased over the last 20 years. Pharmaceutical companies market FDC drugs shortly before the generic versions of the single ingredients enter the market extending the patent and exclusivity life of drugs now included in the combination.

Moir 2016 [109]

Retrospective empirical case study exploring two types of secondary ‘evergreening’ patents—new formulations and closely related chemical variants. Quantifies the cost of such evergreening patents to the Pharmaceutical Benefits Scheme.

Two evergreening venlafaxine patents led to an additional transfer of at least A$150 million from Australian taxpayers to Pfizer, beyond the transfers supported by the original new molecule patent. One was a formulation patent and the other a metabolite of the original medicine. Omeprazole patents have led to a delayed generic entry cost to taxpayers of an estimated A$1.1 billion over8 years. Over the 12-year period since the isomer, esomeprazole, came onto the market, the additional cost to the taxpayer from prescribing this higher priced molecular variant was A$1.8 billion.

Sampat and Shadlen 2015 [110]

Retrospective comparison of the differences between primary and secondary patent grant rates in three developing countries to differences in three patent offices (the US, Europe, and Japan) that do not have measures to limit secondary patents.

Grant rates for secondary patents were lower than those for primary patents in Argentina, but not in India or Brazil. For all three countries, measures to restrict secondary patents have limited effectiveness and are not the main factor in determining grant rates – other procedural issues are more important. Includes comparison grant rates for secondary patents in developing countries for “twins,” (the same applications filed in different jurisdictions).

Sampat and Shadlen 2017 [111]

Retrospective study to compare national approaches toward secondary pharmaceutical patents and examine outcomes of secondary patent applications in India and Brazil.

Brazil is less likely to grant applications than India, but in both countries the measures designed to limit secondary patents are having little direct effect. There may be cause for concern that laws on the books are not having the expected impact on patent outcomes in practice. At the drug level, the effects of countries’ approaches toward secondary patents needs to be understood in the context of their broader approaches toward TRIPS implementation, including when and how they introduced pharmaceutical patents in the 1990s and 2000s.