Open Access

Could patents interfere with the development of a cardiovascular polypill?

  • Reed F. Beall1, 2, 3Email author,
  • Jon-David R. Schwalm4,
  • Mark D. Huffman5,
  • Tara McCready4,
  • Salim Yusuf4 and
  • Amir Attaran1, 2, 3
Journal of Translational Medicine201614:242

DOI: 10.1186/s12967-016-0997-3

Received: 5 June 2016

Accepted: 2 August 2016

Published: 18 August 2016

Abstract

Background

The Wellcome Trust, the World Health Organization, and cardiologists have advocated for the idea of a “polypill” containing multiple cardiovascular drugs to be co-formulated into a single pill for over a decade. Some cardiologists have asserted that the drugs commonly considered for inclusion into such a polypill are older and therefore free of patent protection. We tested this assertion. This project was requested by the World Heart Federation (WHF).

Methods, data and materials

Two cardiologists from the WHF provided a list of 48 cardiovascular drugs for evaluation. We designated the United States and Canada as the base jurisdictions for this patent study. We linked patent data from these countries’ national medicine patent registers to patent information in over 96 other countries using Derwent and INPADOC via Thomson Innovation. We expanded our study beyond the aforementioned data linkage through a systematic search of the World Intellectual Property Organization’s PatentScope, which was based primarily upon the drugs’ active ingredient names.

Results

In the United States and Canada, eight of the drugs were only available in the patent-protected, brand name formulation in one or both countries. Another 21 drugs had relevant patents, but generic equivalents were nevertheless available. Only 19 drugs (40 %) appeared entirely post-patent. Broadening the co-formulation searches globally, the overwhelming majority of drugs (40/48) were mentioned in patent applications for cardiovascular drug combinations.

Conclusion

The assertion that most of these cardiovascular drugs are post-patent is accurate, but only in the sense that many of the original patents on these active ingredients have expired and that generic alternatives are usually available. The landscape of patents covering novel (co-) formulations is far more complex, however. Most research and development for cardiovascular combination medicines are likely to be undertaken by companies whose original patents on the active ingredient will soon expire or have recently expired. Cardiologists looking to accelerate polypill development may consider approaching such companies to partner.

Background

There is a major gap between the prevalence of hypertension, and recourse to effective treatment, particularly in developing countries, where 80 % of the disease burden lies [1, 2]. To address this, many have called for simplifying both the prescribing of and adherence to treatment by co-formulating (i.e., combining) several drugs into a single “polypill,” rather than 3–7 pills taken individually [36]. Triple and even quadruple co-formulations have been developed for conditions such as HIV/AIDS and tuberculosis, and are credited with improved treatment outcomes [7, 8]. A number of clinical trials [2, 9, 10] and meta-analyses [11, 12] of different polypill co-formulations suggest that the same strategy can be helpful for the treatment of hypertension and for the primary and secondary prevention of cardiovascular disease (CVD) [13, 14]. A polypill can also improve patient adherence, and it can reduce the risk of adverse drug interactions in patients taking multiple medications [15]. Given the potential to reduce cardiovascular events and the associated cost of care, public investment into the development of a polypill has been shown to be cost-effective [16]. Indeed, the World Health Organization has been calling for the development of a polypill for over a decade [17].

But while there is large appetite from the public health community for a polypill, no such thing is commonplace in today’s global pharmaceutical market. Why is this? Are there patent barriers to market entry? Experts on the treatment of CVD have stated that the drugs under consideration for inclusion in cardiovascular polypill prototypes are no longer covered by patents [3, 6, 18], but this presumption has not been rigorously tested. A very recent study was published that investigated the patent situation on five cardiovascular medicines in the United States and Europe, but did not extend beyond these drugs and geographic regions [19]. Several publications, both academic [4, 20] and otherwise [21, 22], have rightly called for a broad and global understanding of the polypill patent situation. This article is intended to address this need. It is written for a broad audience while bearing in mind that this project was undertaken at the request of the World Heart Federation (WHF).

Methods, supporting materials, and data availability

We began by independently consulting two expert cardiologists (JDRS, MDH)—who both participated in a workshop on the polypill endorsed by the WHF—on what drugs are of particular interest for co-formulating. We used the union of their drug lists (n = 48 drugs) as the focal point for this patent study.

As patent grants vary by country, it is necessary to designate a base legal jurisdiction for patent studies as a starting point for analysis. Consistent with other published methodologies [2329], we set the United States and Canada as our base jurisdictions because medicine patents are uniquely prevalent there. These countries have large pharmaceutical markets, grant a high number of patents annually, and have strong infrastructure for enforcing those patents, making them particularly attractive for pharmaceutical suppliers.

Both countries have publicly available medicine patent registers—the United States Food and Drug Administration’s Orange Book [30] and Health Canada’s Patent Register [31]—that allow users to search by active ingredient name. We therefore searched by each active ingredient name in each database and then recorded the patent information retrieved, if any. We also recorded whether an equivalent generic product was available on the market for each drug using the Orange Book [30] and Health Canada’s Drug Product Database [32]—that is to say, whether the product had already been “genericized” in the United States and Canada respectively. We considered an equivalent to be a generic product with the identical active ingredient(s), (co-)formulation, and strength as the brand name one in question (i.e., the originator’s patented version).

Next, we consulted two commercial-grade international patent search databases covering over 96 countries—INPADOC [33] and Derwent [34]—via Thomson Innovation [35]. These databases group patent filings into “patent families” (i.e., sets of related patents), which is either done automatically by their relationship to an original priority application (as is the case in INPADOC [36]) or is done manually by patent analysts (as is the case in Derwent). Using the union of the patent family groupings of INPADOC and Derwent adds to the robustness of studies such as these, both in terms of the type of patents covered and the countries covered by them [23]. We entered the American and Canadian patent data from those North American medicine patent registers into Thomson Innovation and retrieved the international patent families for each drug. Reasoning that patent protection for each application is unlikely to extend longer than the standard 20-year period, we removed all patents with application filing dates earlier than 1 January 1995.

Thereafter, we reviewed the title and abstract of each “Basic” patent identified by Derwent (i.e., a patent representing the typical one contained within each family). We scored the type of protections typically covered by the patents contained in each family according to their proposal of a new co-formulation (i.e., drug combinations), a new compound (i.e., the active ingredient), a new formulation (e.g., extended release tablet or capsule), a new method of treatment (i.e., using the drug to treat specific conditions), and/or a new manufacturing process.

Both a strength and limitation of the above method is that all patents included are related to currently marketed products. To provide an impression of potentially relevant patent literature that may have been excluded, we conducted supplemental searches in the World Intellectual Property Organization’s (WIPO) PatentScope database [37]. This database contains applications filed by those seeking protection in many or all of the 148 national signatories to the Patent Cooperation Treaty. We built search algorithms to capture patent applications on combinations of the drugs on our list of 48 medicines. Our search protocols are included Additional file 1: Appendix S1.

All of the above patent searches were performed in May and June 2015. Note that there is no objective, definitive point at which such searches have identified all relevant patents. An expert judgment has to be made when to stop. Our results therefore should be taken as a preliminary appraisal, reflecting our search strategy, and should not be regarded by anyone seeking to commercialize these drugs as a substitute for obtaining independent legal advice. Our raw datasets are available in this article’s supplementary materials (Additional file 2).

Results

The drugs’ patent/genericized status as single formulations in the United States and Canada

We found that eight of the 48 drugs (17 %) were available only as a brand name, patent-protected formulation in one of the base jurisdictions (the United States or Canada) (see Fig. 1). Olmesartan was the only drug available exclusively in the brand name in both countries.
Fig. 1

The 48 cardiovascular drugs as single formulations categorized by presence of generic competition and active patent listings in the United States or Canada

Also shown in Fig. 1 are the 16 drugs (33 %) for which relevant patents were located in the United States or Canada, but had nevertheless been genericized. As for the remaining cardiovascular drugs (24 of 48 or 50 %), we located no valid patents and observed that the markets had indeed been genericized.

The drugs’ patent/genericized status as co-formulations in the United States and Canada

As for fixed-dose combination (FDC) products containing one or more of the 48 drugs of interest, we found ten drugs (21 %) for which the only co-formulation(s) available in the United States or Canada was the patent-protected, brand name product (see Fig. 2). An additional ten drugs (21 %) were contained in one or more patented-protected FDCs, but had been genericized. For the majority of the cardiovascular drugs (28 of 48, or 58 %) investigated, however, we either located no patents using our methodology or observed that no co-formulations containing the drug in question were on the market.
Fig. 2

The 48 cardiovascular drugs in FDCs categorized by presence of generic competition and active patent listings in the United States or Canada. 1 This drug has one or more patents listed for it as a single formulation matched with an absence of generic alternatives in the concerned market (see Fig. 1). 2 While this drug has one or more patents listed for it as a single formulation, there are nevertheless generic alternatives available in that market (see Fig. 1)

Patent filings by type of protection and by country

Table 1 shows the type of protections covered by the patent filings contained in the INPADOC and/or Derwent international patent families relating to the relevant US or Canadian marketed products in question. Patent protection on these drugs’ active ingredients was rare, but in some cases, not all patents had expired globally, even in North America.
Table 1

The 48 cardiovascular drugs categorized by type of patent protection and country

Drug

United States

Canada

Other countries

Patentsa

Patentsa

Patentsb

Co-formulation

Compound

Formulation

Method

Process

Co-formulation

Compound

Formulation

Method

Process

Co-formulation

Compound

Formulation

Method

Process

Acebutolol

               

Acetylsalicylic acid (aspirin)

  

X

X

   

X

X

   

16

16

 

Amiloride

               

Amlodipine

X

 

X

X

X

X

    

63

1

4

7

4

Atenolol

               

Atorvastatin

X

 

X

X

X

X

 

X

X

X

50

4

53

39

39

Benazepril

X

              

Bisoprolol

               

Bumetanide

               

Candesartan

X

X

 

X

   

X

X

X

1

 

4

10

9

Carvedilol

  

X

X

X

  

X

X

X

  

22

29

13

Chlorothiazide

               

Chlorthalidone

X

    

X

    

31

    

Clopidogrel

  

X

 

X

  

X

 

X

 

11

44

 

44

Enalapril

           

3

   

Eplerenone

X

 

X

X

 

X

 

X

X

 

25

3

25

25

 

Eprosartan

X

 

X

X

X

X

 

X

X

X

7

6

37

42

37

Felodipine

               

Fluvastatin

  

X

    

X

    

36

  

Fosinopril

           

2

   

Furosemide

               

Hydrochlorothiazide

X

    

X

    

60

    

Indapamide

X

    

X

    

37

    

Irbesartan

X

 

X

  

X

 

X

  

23

8

23

  

Lisinopril

           

3

   

Losartan

  

X

 

X

      

2

   

Lovastatin

X

 

X

    

X

  

13

1

12

12

 

Metolazone

               

Metoprolol

               

Nadolol

               

Nebivolol

  

X

    

X

   

1

31

4

 

Nifedipine

               

Nimodipine

               

Olmesartan

X

X

X

X

X

X

 

X

  

29

8

24

8

8

Perindopril

  

X

X

X

X

 

X

X

X

18

 

37

18

 

Pitavastatin

X

 

X

X

X

  

X

X

X

13

2

17

17

10

Pravastatin

   

X

    

X

  

1

 

8

 

Propranolol

  

X

X

   

X

X

   

10

10

 

Quinapril

  

X

X

  

X

    

1

3

3

 

Ramipril

X

  

X

 

X

  

X

 

34

 

34

35

 

Rosuvastatin

 

X

X

X

   

X

X

 

6

50

33

  

Simvastatin

X

    

X

    

19

    

Spironolactone

               

Telmisartan

X

X

X

X

X

X

 

X

X

X

49

6

35

17

36

Torasemide

               

Trandolapril

X

  

X

  

X

  

X

3

  

2

 

Triamterene

               

Valsartan

X

X

X

X

 

X

 

X

X

 

42

7

36

36

 

Total

18

5

20

18

10

14

2

18

14

9

523

120

536

338

200

 

All countries

          

Grand totals

555

127

574

370

219

     

aA “X” means that at least one patent was found fitting into this category on the national patent register. The underline “X” denotes at least one patent was found in the INPADOC and/or Derwent patent family, but current legal status is unknown

bThe numbers below indicate the number of jurisdictions (countries or regional agreements) covered by the patents in the INPADOC and Derwent patent families. Current legal status of these patents is unknown

By far, the most common type of protection afforded by these drugs’ respective patent families pertained to novel formulations or co-formulations. Patents applying to these categories were nearly five times more prevalent as compared to those on the active ingredient. Patents on using the drug as a method of treatment for cardiovascular disease or on a manufacturing process were also much more common than those on the active ingredient.

Nevertheless, as is shown in Table 1, we found no patents of any type whatsoever on 19 of these drugs in the United States and Canada, which cover all drug classes identified by the WHF cardiologists (i.e., statins, antiplatelets, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, beta blockers, and diuretics).

Searching for polypill co-formulation patents globally: WIPO PatentScope

Finally, to extend our analysis beyond the patents related to those listed in the American and Canadian medicine patent registers, we searched WIPO PatentScope for all patent applications that mention combinations of drugs within our list of 48 cardiovascular medicines. (see Additional file 1: Appendix S2 for four common approaches that we observed applicants had taken to construct their patent applications for cardiovascular FDCs.)

The overwhelming majority of the drugs (40 of 48, or 83 %) were identified in the co-formulation patent applications returned from WIPO PatentScope, either by active ingredient name or by drug class. Only eight drugs were unmentioned, all of which were older diuretics (amiloride, bumetanide, chlorthalidone, eplerenone, furosemide, metolazone, spironolactone, torasemide, triamterene). The remaining 3 (chlorothiazide, hydrochlorothiazide, indapamide) were identified as the diuretic of choice in many proposed co-formulations, especially hydrochlorothiazide.

Discussion

Cardiologists’ perception [3, 6, 18] that the drugs being considered for CVD polypill co-formulations are post-patent has some empirical merit, but only in the sense that many of the original patents on the active ingredient(s) have expired and that the majority of these drugs have been genericized. This overlooks, however, that other forms of patent protection (i.e., formulation, co-formulation, method of treatment, manufacturing process) are more prevalent and can carry on for years after the expiration of the original patents on the active ingredient(s). We found that only 19 of the 48 drugs (40 %) were totally patent free in the base jurisdictions according to our methodology (see Table 1) and that most of the drugs (40 of 49, or 83 %) could be found on co-formulation patent applications filed through WIPO. When these secondary tiers of patenting are taken into account, it is more common to find patent filings than none whatsoever.

What is the significance of this finding for polypill advocates like the WHF who see promise in that treatment in developing countries? Below we discuss two perspectives on the patent system—for shorthand, the “competitive” versus “cooperative” perspectives—which differently inform two corresponding courses of action based on the findings and data presented in this report.

The “competitive” perspective is that patents represent strong, if temporary, barriers for others seeking to develop a technology and disseminate it widely. Patent owners possess exclusive rights to seek financial compensation in the law courts from those who infringe their technology. In this perspective, advocates of a CVD polypill should be prepared to deal with risk adverse pharmaceutical companies, who would likely not want to develop products that infringe upon these rights. Any patent is therefore a disincentive.

Based on this view of the patent system, our results, such as those in Table 1, may be read as a road map of existing obstacles to polypill co-formulating, while the non-shaded areas of Figs. 1 and 2 represent the patent-free freedom to operate. One could, then, work within the latter subset to propose a new cardiovascular FDC, which dodges the patent barriers. In doing so, advocates would be well advised to work with pharmaceutical firms with proven track records in the chemistry, manufacturing and controls aspects of making pharmaceuticals and with experience obtaining product registration. While all the major pharmaceutical companies have these capacities, some generics firms do as well. As of writing, one generics company (Ferrer) is already making FDCs that meet the requirements of stringent regulatory authorities in Europe, as are several India-based firms albeit without satisfying stringent regulatory authority standards [17, 38].

The “cooperative” perspective is that the patent system serves to incentivize new innovation, products and commercial activities. Patent owners acquire rights so as to make a business case for investment and commercialization. In this perspective, advocates of a CVD polypill should try to piggyback onto efforts that maximize the revenue pharmaceutical companies can obtain from their patent holdings, but in such a way that allowances are made for access to medicines in poorer countries.

Based on this view of the patent system, the shaded areas of Figs. 1 and 2 represent not barriers, but opportunities, because the patent holder’s monopoly brings with it a company that already has solved the technical and regulatory issues of their patented drug, and likely has the wherewithal and business interest to drive forward a new FDC including that drug. Indeed, evidence shows that companies become most receptive to develop new co-formulations as primary patents come close to expiring, so as to extend (or “evergreen”) market exclusivity [39]. See Table 2 for the age original patents on the active ingredients of the 48 drugs’ in descending order according to the Merck index [40]. There is empirical evidence that co-formulating is already happening for the most recently expired patents on the active ingredients: Daiichi Sankyo has recently introduced Tribenzor (amlodipine + hydrochlorothiazide + olmesartan), and Novartis has introduced Exforge HCT (the same, but substituting valsartan for olmesartan). Advocates would be well advised to create mutually beneficial arrangements with the pharmaceutical companies whose original patents on the active ingredient are drawing to an end, both to innovate polypills, and to bring these to market in developing countries at an affordable price. A clear lesson learned from the global campaigns for access to HIV/AIDS, malaria and other medicines is that companies can reconcile revenue maximization in rich countries with reduced revenue expectations or even philanthropic concessions in poor countries. They can do this by out-licensing their patents in the latter, refraining from enforcing their patents in certain regions, and/or offering substantial price reductions based on ability to pay (tiered pricing) [4145]. Whatever access strategy is chosen, patents can be actively managed to serve as springboards for access campaigns, rather than managed as just barriers.
Table 2

Merck index active ingredient patent listing for the 48 cardiovascular drugs

INN

Latest patent grant year provided

International INPADOC family application date range

Patent numbers provided

Olmesartan

1997

1992–2011

EP503785, US5616599

Valsartan

1995

1991–2010

EP443983, US5399578

Candesartan

1993

1991–2006

EP459136, US5196444

Eprosartan

1993

1990–2001

EP403159, US5185351

Irbesartan

1993

1990–1999

WO9114679, US5270317

Atorvastatin

1993

1990–2007

EP409281, US5273995

Rosuvastatin

1993

1992–2003

EP521471, US5260440

Losartan

1992

1987–1999

EP253310, US5138069

Telmisartan

1992

1991–2011

EP502314

Fosinopril

1991

1988–1995

EP 304063, US5011930

Pitavastatin

1991

1988–1995

EP304063, US5011930

Trandolapril

1990

1981–1994

EP84164, US4933361

Clopidogrel

1989

1982–1998

EP99802, US4529596, EP281459, US4847265

Fluvastatin

1988

1983–1995

WO8402131, US4739073

Nebivolol

1987

1984–2004

EP145067, US4654362

Ramipril

1986

1982–1994

EP79022, US4587258

Amlodipine

1986

1983–1998

EP89167, US4572909

Perindopril

1985

1979–1993

EP49658, US4508729

Carvedilol

1985

1978–1994

DE2815926, US4503067

Eplerenone

1985

1984–2004

EP122232, US4559332

Simvastatin

1984

1980–1994

EP33538, US4444784

Benazepril

1983

1982–1993

EP72352, US4410520

Enalapril

1983

1979–1998

EP12401, US4374829

Lisinopril

1983

1979–1998

EP12401, US4374829

Quinapril

1982

1981–1996

EP49605, US4344949

Pravastatin

1982

1980–1996

DE3122499, US4346227

Felodipine

1981

1978–1994

EP7293, US4264611

Bisoprolol

1981

1976–1993

BE859425, US4258062

Lovastatin

1980

1978–1998

US4231938

Torasemide

1977

1974–1994

DE2516025, US4018929

Metoprolol

1976

1932–1977

DE2106209, US3998790

Nadolol

1976

1971–1979

DE2258995, US3935267, DE2421549

Nimodipine

1974

1971–1977

DE2117571, US3799934

Acebutolol

1974

1967–1974

ZA6808345, US3857952

Atenolol

1974

1969–1975

DE2007751, US3663607, US3836671

Bumetanide

1974

1968–1974

DE1964503, DE1964504, US3806534

Indapamide

1971

1968–1969

FR2003311, US3565911

Propranolol

1970

1962–1967

BE640312, BE640313, US3337628, US3520919

Nifedipine

1969

1967–1969

ZA6801482, US3485847

Amiloride

1967

1962–1981

BE639386, US3313813

Metolazone

1967

1966–1967

US3360518

Acetylsalicylic acid (aspirin)

1966

1959–1964

DE236196, US2890240, US3235583

Hydrochlorothiazide

1964

1962–1965

US3025292, US3163645, DE1163332, US3164588, US3043840

Triamterene

1963

1960–1964

US3081230

Chlorthalidone

1962

1957–1962

US3055904

Furosemide

1962

1959–1964

DE1122541, US305888

Spironolactone

1961

1960–1961

US3013012

Chlorothiazide

1957

1957

US2809194

We do not consider the “cooperative” and “competitive” scenarios mutually exclusive; rather they are complementary and should both be pursued. But both of them require that advocates make it extremely clear exactly which medicine combinations are best for an FDC. That choice has to be based on strong scientific consensus of the most clinically rational combinations, but not necessarily unanimity, and must strike a balance between the best therapeutic outcomes (for patient treatment success) and widespread suitability of the formulation (for population health coverage). Clear consensus is a true sine qua non, because whether seen through the eyes of a branded or generic company, advocates are calling on them to invest millions of dollars in FDC development and registration—and very simply put, companies will only sink that money when there is consensus guidance that says “the combination of A plus B plus C is satisfactory”, rather than equivocal guidance that says “the combination of A or B, plus C or D, plus E or F, but not if F is combined with C”.

The endorsement of advocates, or a coalition of advocates, to recommend a particular CVD co-formulation would likely appeal to drug makers and have a very significant impact on their willingness to invest. Since one would be endorsing a choice of co-formulation, and not a product, there is no conflict of interest in doing so. That would be a valuable step, whether pursuing a FDC built upon the “competitive” viewpoint of selecting only unpatented drugs over which nobody has exclusivity, or upon the “cooperative” viewpoint of selecting a drug precisely because it is patented and somebody has exclusivity. Our previous research in bringing low-cost new medicines to developing countries has shown that, depending upon circumstances, patent-centered strategies for improving access to medicines can be just as effective as patent-negating ones [41, 46, 47].

Conclusion

Our study has tested the assertion that the drugs under consideration for polypill co-formulating are older, are post-patent, and have been genericized. For the original active ingredient patents, this is largely true, but our findings show that secondary patenting on these medicines is prevalent, and this includes large numbers co-formulation patents by generic and brand name companies alike.

We have suggested two strategies based on the empirical data provided by this study for global public health entities like the WHF who are in pursuit of developing a polypill, and these strategies can be undertaken simultaneously. Our impression, however, is that others attempting to advance polypill development have relied most heavily upon variants of the first strategy. We suggest a more balanced approach, set upon two parallel tracks, in which patents are viewed both as barriers and as opportunities, depending who the commercial partner is.

Abbreviations

CVD: 

Cardiovascular disease

FDC: 

Fixed-dose combination

INPADOC: 

INternational PAtent DOCumentation database, which is maintained by the European Patent Office

HIV/AIDS: 

Human immunodeficiency virus infection and acquired immune deficiency syndrome

WHF: 

The World Heart Federation

WIPO: 

The World Intellectual Property Organization

Declarations

Authors’ contributions

RFB, SY, and AA conceived and designed the study. RFB, JDRS, MDH collected the data. RFB and AA analyzed the data. RFB wrote the first draft of the manuscript. All authors contributed to revising the manuscript. All authors read and approved the final manuscript.

Acknowledgements

Authors declare that each of their roles in the development of this manuscript satisfies the ICMJE criteria for authorship. No direct funding was received specific to this manuscript; however, this article is relevant to RFB’s doctoral studies, which have been funded through a Vanier Doctoral Scholarship by the Canadian Institutes of Health Research (CIHR) of the Government of Canada.

Competing interests

JDS, TM, and SY have declared that PHRI receives funding for investigating the polypill from Cadila, but the authors have not received any personal compensation, stocks or share or employment with Cadila or any other company. SY received an honorarium and travel expenses once to attend a meeting in the last 5 years. SY is listed as an inventor on patents relating to the treatment of cardiovascular disease. MDH receives support from the World Heart Federation to serve as its senior program advisor for its Emerging Leaders program, which is funded by unrestricted educational grants from AstraZeneca, Boehringer Ingelheim, and Bupa. All other authors (RFB and AA) have nothing to declare.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Population Health Program, University of Ottawa
(2)
Faculties of Law, University of Ottawa
(3)
Faculties of Medicine, University of Ottawa
(4)
Population Health Research Institute (PHRI), Hamilton Health Sciences, McMaster University
(5)
Feinberg School of Medicine, Northwestern University

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