TWO STANDARDS OF CARE - Home - CTAC€¦ · are living with HIV/HCV co-infection. Procedural and institutional barriers have resulted in two standards of care – one for people living

TOWARD TREATMENT EQUITY FOR PEOPLE LIVING WITH HIV/HCV CO-INFECTION

TWO STANDARDS OF CARE:

TOWARD TREATMENT EQUITY FOR PEOPLE LIVING WITH HIV/HCV CO-INFECTION

TWO STANDARDS OF CARE:

http://www.ctac.ca

CTAC is Canada’s national civil society organization addressing access to treatment, care and support for people living with HIV and HCV. CTAC meaningfully engages community members, service providers, policymakers and researchers to identify, develop and implement policy and program solutions.

©2013, CTAC (Canadian Treatment Action Council).

All rights reserved.

Contact CTAC

1-877-237-2822 • www.ctac.ca

WriterPaul Sutton

Design, Layout and IllustrationNicki Roswell, Phoenix Creative

TranslatorChristopher Ellis

ReviewersKimberly Bennett, Jolene Donatelli, Marilou Gagnon, Derek Hodel, Christian Hui, Jim Kane, Shan Kelley, Michel Long, Doug McColeman, Andrew Miao, Ron Rosenes, Michael Sangster, Barbara Santosuosso, David Smith

Permission to Reproduce

This document is copyrighted. It may be reprinted and distributed in its entirety for non-commercial purposes without prior permission, but permission must be obtained to edit or otherwise alter its content. The following credit must appear on any reprint: This information was provided by CTAC. For more information contact CTAC at 1-877-237-2822 or www.ctac.ca.

CONTENTS

Introduction and Co-infection Background

Two Standards: Clinical Trial Design

Two Standards: Health Technology Assessment and Formulary Approvals

Treatment Delayed is Treatment Denied: Policy Options

Moving Forward and Additional Resources

References

5

9

19

25

27

29

Two Standards of Care 5

We are in the middle of unprecedented drug development to treat hepatitis C, with many expecting a functional cure for the virus within the next decade. Hundreds of molecules with the potential to become viable treatments are under investigation by pharmaceutical developers and, as of this writing, as many as 38 new hepatitis C medications are in various phases of clinical trials.1

This exciting news is not so bright for people who are co-infected with HIV and hepatitis C. As a result of clinical trial designs that delay inclusion of people who are living with co-infection until a new treatment has been proven viable with hepatitis C alone, people living with co-infection gain access to new hepatitis C treatment much later. These delays are exacerbated by the Common Drug Review (CDR) and public formulary decision-making that has explicitly recommended against using new hepatitis C treatments for people living with co-infection until clinical trials catch up.

HIV and hepatitis C co-infection presents immediate, drastic health challenges unlike those seen in people living with hepatitis C alone. The hepatitis C virus progresses very slowly in many people living with mono-infection, with symptoms not showing up for many (20-40) years, if at all; however, HIV accelerates hepatitis C progression to the point that many co-infected people are shown to have significant liver fibrosis, cirrhosis or even liver cancer within 10-15 years of infection.

While improved treatments are necessary for all people living with hepatitis C, this is particularly true for people who are living with HIV/HCV co-infection. Procedural and institutional barriers have resulted in two standards of care – one for people living with mono-infection, and a much worse standard for people living with co-infection. This position paper explains why these two standards of care have emerged and makes pragmatic recommendations to accelerate clinical trials and CDR decision-making to allow co-infected people to benefit from the latest technologies available.

This position paper explains:

• How clinical trial designs often cause unnecessary delays in evaluating the safety and efficacy of new hepatitis C treatments for people who are living with co-infection

• How health technology assessment organizations like the CDR, as well as public formularies, exacerbate these delays by limiting coverage for co-infected people, preventing doctors from doing what is right for their patients.

• Pragmatic changes that can be made to clinical trial designs and health technology assessment decision-making that will assure timely access and equitable treatment for people living with co-infection

INTRODUCTION


CO-INFECTION BACKGROUND

HIV/HCV co-infection is a serious medical condition affecting an estimated 20% of all people living with HIV in Canada.2 Since the introduction of effective antiretrovirals in 1996, liver disease and other non-AIDS related cancers have become the leading causes of death. While liver mortality for people living with HIV is often related to long-term side effects of antiretroviral therapies, much mortality is attributed to complications related to HIV/HCV co-infection.3-5

Of all people determined to have acquired HIV through sharing injection drug equipment, 87.7% are co-infected with HIV/HCV. Because of this, higher rates of co-infection are found amongst people and/or within institutions where HIV transmission is associated with shared injection drug equipment, especially where harm reduction services are limited or unavailable (such as in prisons or in rural/remote areas).7-13 Multiple vulnerabilities to HIV/HCV co-infection are generated in places where policy responses are inadequate to provide substance and sexual health programs to nurture HIV and hepatitis C knowledge within communities, coupled with reduced access and equity due to colonization, racism and other forms of inequality and stigma.14

Indeed, it can be said that people living with HIV in Canada who have experience sharing injection drug equipment are actually much more likely to be living with HIV/HCV co-infection than HIV alone. Hepatitis C disease progression is accelerated by HIV/HCV co-infection, and people living with HIV/HCV co-infection face tremendous inequity in accessing under-resourced

medical, income, housing and food security supports needed to achieve better health outcomes for people living with HIV/HCV co-infection. Consequently, health responses developed must be competent to address broad determinants of health, and ensure all people have full access to health and social services – including, perhaps especially, timely and affordable access to treatment.


This position paper addresses the two main reasons access to new hepatitis C treatments is delayed for people living with HIV/HCV co-infection: clinical trial design and health technology assessment decision-making (specifically, that of the CDR).

CLINICAL TRIALS: BACKGROUND

In pharmaceutical development, after a promising molecule’s pharmacodynamics and pharmacokinetics15 have been deemed appropriate to test for safety and efficacy in human beings, it is put through a series of clinical trial phases. Generally speaking, each phase involves the following:

• Phase 1 trials test a new medication on healthy volunteers to determine safety, efficacy and dose ranges (for example, how much of a medication is required in order for it to have effect). These trials are very small, including anywhere from 20 to 100 people.

• Phase 2 trials test safety and efficacy among the patients with the condition a new medication is intended to treat (for example, people living with HIV and hepatitis C co-infection). These trials, controlled by a placebo (that consists of the “standard of care”, in other words, the treatment that is currently available), experiment with different doses, drug combinations and treatment lengths. These trials are somewhat larger, including anywhere from 100 to 300 people.

• Phase 3 trials occur if safety and efficacy was demonstrated during Phase 2 trials. If so, the most promising treatment regimen(s) identified during Phase 2 trials are tested against a group receiving the “standard of care” placebo. These trials are substantially larger, aiming to show treatment efficacy in a much wider variety of patients, including anywhere from 1000 to 2000 people.

After Phase 3 trials have been completed and show favourable results, pharmaceutical developers can apply to Health Canada for a Notice of Compliance(NOC) – certification that approves a new medication for sale or “marketing” in Canada. Phase 0-3 trials are known as “pre-market” or “registrational trials”; sometimes, new medications are also mandated to undergo Phase 4 trials (also known as “post-market surveillance”), monitoring the safety and long-term effects of medications after they have entered the marketplace and are used in “real life” settings.16

Not routinely mandated by regulators like Health Canada, CTAC has long encouraged the regulator to mandate Phase 4 trials by establishing a Post-Market Surveillance System17. As much information as possible must be gleaned about new medications, both in terms of positive and negative effects, so that it is easier for consumers to report and manufacturers to respond to adverse events and unmet areas of clinical need."18

TWO STANDARDS: CLINICAL TRIAL DESIGN

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EQUITY IN CLINICAL TRIALS: ONGOING CHALLENGES

Bringing a new medication from discovery to market requires significant investment. Although exact cost figures for drug development are largely unknown, reports estimate it costs between $500 million and $2 billion to bring a new medication from discovery to market.19 20 Clinical trials often establish inclusion and exclusion criteria that maximize the number of “ideal patients” enrolled in the study. This practice, in addition to the application of a "modified intention-to-treat" analysis21 attempts to show safety and efficacy results in the most ideal possible circumstances, maximizing investment and minimizing challenges associated with the messiness of everyday life.22

People living with HIV/HCV co-infection are not considered “ideal patients” when it comes to clinical trials for new hepatitis C therapies. HIV/HCV co-infection has been considered a “confounding factor” in hepatitis C drug development, in part because the previous standard of care (ribavirin and pegylated interferon) was particularly ineffective in treating co-infected people living with genotype 1 hepatitis C. People who use drugs are not considered “ideal patients” for clinical trials either and are excluded even though much research demonstrates a multidisciplinary care approach produces strong treatment outcomes for substance-involved people.23-26 However, numerous people living with HIV/HCV co-infection, use substances and as a result, clinical trial exclusions based on substance involvement create an additional barrier to including co-infected people in clinical trials.

There exists extensive literature on equity and clinical trial inclusion, with a specific focus on how many clinical trials have typically excluded women and older people. In the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans, the Government of Canada’s Panel for Research Ethics identifies conditions under which it is inappropriate to exclude women, children and the elderly from research, including guidelines to manage informed consent.27 However, the policy statement does not identify “harder to treat” patients or people who use drugs as groups that are inappropriate to exclude from research.

While the reasons for including only “ideal patients” in clinical trials are pragmatic and clear, in essence, it is thought that testing new medications with “ideal patients” will result in the least amount of delays in drug development and regulatory approval and it is easier to have new medications approved for “harder to treat” people once they are available in the first place. Promising clinical trial design alternatives (such as the sofosbuvir clinical trials discussed below) that may accelerate testing and access for people living with HIV/HCV co-infection.


BOCEPREVIR AND TELAPREVIR TRIALS: LESSONS LEARNED

In March 2007, the Sitges Statement, proceeding from a meeting of researchers and civil society leaders involved in the European AIDS Treatment Group (EATG) was released, calling for “regulatory requirements or recommendations for studying novel HCV therapies in HIV-positive people prior to their approval for treatment of HCV monoinfection” and that testing occurs “once results from Phase 2B studies are known, and there are indications from earlier toxicology, pharmacokinetic and drug-drug interaction studies that the specific agent, or agents, under investigation will not have the potential for significant drug-drug interactions, or other toxicities relevant to HIV.”28

The Statement also recommends pharmacokinetic and drug-drug interactions take place as early as possible. At a subsequent EATG meeting in 2012, in addition to assessing promising new HCV treatments for people living with HIV/HCV co-infection, the group repeated the need for regulatory requirements to ensure new HCV treatments are expediently tested in co-infected people.29 Looking in-depth at the clinical trial design for boceprevir and telaprevir, we can see some of the consequences associated with belatedly initiating trials amongst people living with HIV/HCV co-infection. In order to conduct this analysis, we have collected the start and primary completion points of each of the Phase 2 and 3 studies for boceprevir and telaprevir, the total number of patients enrolled, and we have selected relevant exclusion criteria. We have selected Phase 2

and 3 studies for analysis to provide time points for analysis that take place after initial pharmacodynamic and pharmacokinetic studies have demonstrated the new medications are, in fact, viable.30

After Phase 2 trials identified ideal dosing and treatment duration for triple-therapy with ribavirin, pegylated interferon and boceprevir or telaprevir, boceprevir Phase 3 trials commenced in August 2008 with people living with hepatitis C genotype 1 mono-infection who were treatment naive or had failed previous therapy. Telaprevir Phase 3 trials commenced with treatment naive patients in March 2008 and with people who had failed previous therapy in October 2008. People living with HIV/HCV co-infection were excluded from these initial Phase 3 trials for both boceprevir and telaprevir. Although the primary endpoint for the telaprevir trials in people living with mono-infection came months after the boceprevir endpoint, Vertex Pharmaceuticals’ approval filing to the United States Food and Drug Administration (FDA) came just 12 days after Merck made its filing for boceprevir. In Canada, Vertex’s submission for a NOC from Health Canada took place in January 2011, three weeks after Merck’s filing, although the delay could be accounted for in late December organizational closures.

Despite impressive and very optimistic efficacy results from both boceprevir and telaprevir, Phase 2 clinical trials with people living with HIV/HCV co-infection did not commence until both medications had been in Phase 3 trials with HCV mono-infected people for

12 CTAC

more than one year. It is important to keep in mind that boceprevir and telaprevir were the first hepatitis C direct-acting antivirals (DAAs) of their kind to be examined in clinical trials and while this can, to an extent, explain a conservative approach, this clinical trial design promotes delayed access for people living with HIV/HCV co-infection, as warned in the Sitges Statement.

Importantly, in part due to drug-drug interactions associated with boceprevir and some HIV treatments and the significant skin-related adverse events associated with telaprevir, Phase 2 trials of boceprevir and Phase 3 trials of telaprevir with people living with HIV/HCV co-infection have been extended until September 2014. While both trials have resulted in instructive data that has led many physicians to administer boceprevir and telaprevir with co-infected people off-label (see Two Standards: Health Technology Assessment on page 19 and Formulary Approvals and Treatment Delayed is Treatment Denied: Policy Options on page 25 for further explanation), as of this writing, boceprevir and telaprevir are being prescribed to people living with HIV/HCV co-infection prior to the conclusion of clinical trials. Commencing trials with people living with HIV/HCV co-infection at the conclusion of Phase 2b trials in mono-infected people, as advocated in the Sitges Statement, would have mitigated these delays.

Boceprevir and telaprevir are being prescribed to people living with HIV/HCV co-infection prior to the conclusion of clinical trials.


Table 1. HCV Clinical Trial Design for boceprevir, telaprevir and sofosbuvir (including timelines, number of patients enrolled, and selected exclusion criteria)

In prior non-responders:31

Start: September 2005 Completion: July 2007 Number Enrolled: 357

PH

ASE

2 T

RIA

L D

ESIG

N

Phase 2 study of safety and viral kinetics32

Start: December 2005 Completion: April 2006 Number Enrolled: 12

In treatment-naive patients:34 Start: January 2007 Completion: August 2008 Number Enrolled: 765

Exclusion Criteria (Selected):

Prior hepatitis C treatment; co-infection with HIV or HBV; liver decompensation; diabetes; mental health diagnosis; substance involvement

BOCEPREVIR


Patients with cirrhosis, HBV, HIV; women who are pregnant or nursing; African Americans; previous treatment with an investigational protease inhibitor; prior relapse post-treatment; advanced liver disease; pre-existing psychiatric condition (diagnosed)

TELAPREVIR


Contraindications to PEG or RBV

Observational to determine viral kinetics of triple-therapy (PEG+RBV+TEL)

SOFOSBUVIR

Note: A fourth arm studied patients with genotype 2 and 3, who were also included in arms 1-3. Results are not discussed in detail because clinical trials for boceprevir and telaprevir are only being given to people living with HCV genotype 1.

In treatment-naive patients:35 Start: June 2006 Completion: February 2008 Number Enrolled: 263


Co-infection with HIV or HBV; prior treatment or use of any investigational hepatitis C treatment; contraindications to PEG and/or RBV; liver decompensation, cirrhosis or cancer; alcohol use

In treatment-naive patients:33

Start: August 2010 Completion: May 2012 Number Enrolled: 147


Co-infected with HIV or HBV; previous treatment with PEG/RBV; chronic liver condition; significant immunological condition; organ transplantation, clinically significant allergy to nucleoside/nucleotide drugs; pregnant or nursing, participation in another investigational trial for 3 months

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In treatment naive patients:36

Start: August 2008 Completion: May 2010 Number Enrolled: 1472


Start: March 2008 Completion: May 2010 Number Enrolled: 1095

In patients who failed treatment previously:39 Start: August 2008 Completion: April 2010 Number Enrolled: 404


Same as above, except: past discontinuation of PEG or RBV due to adverse event; treatment with any investigational HCV medication in past 30 days

In patients who failed treatment previously:40

Start: October 2008 Completion: July 2010 Number Enrolled: 663


Same as above, except: must have failed at least 1 PEG+RBV therapy; exhibits more than one HCV genotype; requires to be treated with corticosteroids


Start: June 2012 Completion: April 2013 Number Enrolled: 328

PH

ASE

3 T

RIA

L D

ESIG

N

BOCEPREVIR TELAPREVIR SOFOSBUVIR


Co-infected with HIV or HBV; any previous HCV treatment; enrolled in any other clinical trials; liver decompensation; diabetes; diagnosed mental health condition; substance involvement; cancer (last 5 years); women who are pregnant or nursing; pancreatitis; working on or family member working on study

Exclusion Criteria (Selected): Co-infected with HIV or HBV; any previous HCV treatment; contraindication to PEG or RBV; hepatic decompensation; transplant; any other condition deemed to have potential negative impact on patient

Exclusion Criteria (Selected): Same as above, except: includes people living with HCV genotypes 1, 4, 5 and 6; specific contraindication to alcohol and other substance involvement; does not list HIV seropositivity as exclusion

Table 1. HCV Clinical Trial Design for boceprevir, telaprevir and sofosbuvir cont'd


Phase 2 (in treatment naive patients):41

Start: November 2009 Completion: October 2012 Number Enrolled: 99

Phase 2 (in treatment naive patients):42

Start: October 2009 Completion: November 2012 Number Enrolled: 68

Phase 1/2 HIV drug interaction study:43

Start: March 2012 Completion: November 2013 Number Enrolled: 80

Phase 2 (In patients who failed treatment previously):44

Start: March 2011 Completion: September 2014 Number Enrolled: 69

Phase 3 (treatment naive, relapsers, partial and null responders):45

Start: April 2012 Completion: May 2014 Number Enrolled: 160

Phase 3 (treatment naive):46

Start: July 2012 Completion: February 2014 Number Enrolled: 230

Note: Up to 20% of patient cohort includes people with cirrhosis.

CO-I

NFE

CTIO

N T

RIA

L D

ESIG

NBOCEPREVIR TELAPREVIR SOFOSBUVIR

Note: The United States NIAID is conducting an ongoing Phase 4 trial comparing safety and efficacy of boceprevir triple-therapy between HCV mono-infected and HIV/HCV co-infected people until September 2016 with 200 patients enrolled.

Studying drug interactions of sofosbuvir with: efavirenz, tenofovir and FTC (Atripla); efavirenz, AZT and 3TC; tenofovir, FTC, atazanavir/ ritonavir; tenofovir, FTC, darunavir/ ritonavir; tenofovir, FTC, raltegravir; ribavirn and pegylated interferon


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Submitted: November 10, 2010

Approved: May 13, 2011 47

FDA

APPR

OVA

L

(FO

R M

ON

O-I

NFE

CTIO

N)


Approved: May 23, 2011 48

Submitted: April 8, 2013

Approval: December 8, 2013 49 (expected)

HEA

LTH

CAN

ADA

NO

C

(FO

R M

ON

O-I

NFE

CTIO

N)

To Be Determined

4 years, 4 months (projected)

TIM

E D

IFFE

REN

CE IN

TR

IAL

COM

PLET

ION

(F

OR

MO

NO

- VS.

CO

-IN

FECT

ION

)

3 years, 8 months (projected) 10 months (projected)

BOCEPREVIR TELAPREVIR SOFOSBUVIR

Submitted:December 22, 2010

Granted: July 29, 2011 50

Submitted: January 14, 2011

Granted: August 16, 2011 51



The clinical trial design for sofosbuvir is included in the third column of Table 1 because, in terms of people living with co-infection, these trials compare favourably to those conducted for boceprevir and telaprevir. Like boceprevir, Gilead Sciences acquired sofosbuvir from another developer, Pharmasset, midway through clinical trials. However, the timeline for initiating sofosbuvir clinical trials with people living with HIV/HCV co-infection much more closely followed the Sitges Statement’s recommendations.

Phase 2 trials in treatment naive people living with HCV mono-infection concluded in May 2012. In March 2012, before the primary endpoint of the Phase 2 trials was even reached, Gilead commenced Phase 1/2 trials to test how sofosbuvir interacts with most major first-line HIV therapies currently on the market. This led Gilead to be able to commence Phase 3 trials with treatment naive people living with HIV/HCV co-infection in July 2012, just one month after Phase 3 trials were commenced with treatment naive HCV mono-infected people.

Although clinical trials for sofosbuvir in people living with HIV/HCV co-infection have been extended, similar to the boceprevir and telaprevir trials, the primary endpoint for Phase 3 sofosbuvir co-infection trials is expected in February 2014, six months before the expected endpoint in the boceprevir and telaprevir trials. While it is imperative for Gilead Sciences to increase collaboration with other pharmaceutical companies in order to accelerate the realization of an HCV cure (such as continuing studies of the promising

results seen in sofosbuvir and daclatasvir dual therapy, an interferon-free regimen that has initially shown substantial viability as a cure), as well as include a placebo control arm in future trials, the sofosbuvir clinical trial design is an achievement because it moves us much closer to a model that focuses on the treatment needs of people living with HIV/HCV co-infection.

To put it another way, it is inevitable that new hepatitis C treatments will be particularly important for people living with HIV/HCV co-infection. This demands that pharmaceutical companies plan and implement clinical trials for HIV/HCV co-infection immediately upon primary outcome completion for Phase 2 and Phase 3 registrational trials in people living with hepatitis C alone.


TWO STANDARDS: HEALTH TECHNOLOGY ASSESSMENT AND FORMULARY APPROVALS

Canada’s regulatory environment is the second reason access to new hepatitis C treatments is delayed for people living with HIV/HCV co-infection. In Canada, when a new medication is granted a NOC from Health Canada, approving it for sale or “marketing”, that new medication is submitted to the CDR. The CDR is meant to adjudicate cost-effectiveness of new medications. Decisions made by the CDR are then submitted to participating public drug formularies (including provincial, territorial and federal formularies with the exception of Québec) to inform their own decisions as to whether, and under what conditions, to list a new drug.

Most Canadians living with HIV and hepatitis C access their medications through a public, or “catastrophic” drug plan. Canada does not have a universal pharmacare program. Consequently, most people living with HIV must rely on patchwork public drug plans to afford the high cost of hepatitis C and HIV treatment, especially when impeding risk of ongoing, episodic disability prevents many people from accessing private insurance and/or working for prolonged periods of time. Therefore, access to HIV and hepatitis C treatment in Canada is driven by listing decisions from the CDR and public formularies.

In operation since 2003, the CDR was developed to minimize duplication in health assessments across formularies which, because of Canada’s patchwork drug coverage system, previously conducted their own

safety, efficacy and cost-effectiveness reviews for each new agent. A 2011 article by John-Michael Gamble and others evaluated the CDR’s efficacy at reducing time-to-listing for new medications, as well as drug listing rates before and after the CDR was adopted. While the Gamble study excluded new HIV and hepatitis C medications (where recommendations against listings have been extraordinarily rare),52 it is important to be aware of the overall reduction in new approvals since the CDR has been adopted (81.1% between 1999 - 2003 and 71.3% post-CDR).53

The CDR has been credited with reducing overall time-to-listing in the Atlantic provinces, where formerly, significant access delays occurred. While median time-to-listing in the Atlantic provinces has been reduced by anywhere from 59 to 691 days (Nova Scotia, Prince Edward Island respectively), medians have increased in provinces with formerly efficacious assessment programs, such as Ontario (median increase in time-to-listing is 249 days) and Alberta (median increase in time-to-listing is 170 days). Additionally, Gamble noted a statistically significant increase in time-to-listing in Québec after the adoption of the CDR process, despite its non-participation (median increase in time-to-listing is 65 days). The authors noted “Québec may have been influenced by the CDR, as suggested by a lower positive listing rate after the program was implemented.”54

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Despite the CDR’s best efforts to mitigate approval delays, the critique remains that Canada’s patchwork coverage creates several health care tiers across the country, depending entirely on where you live, whether you access publicly subsidized or privately covered pharmacare (with most private plans providing near-immediate access to new HIV and hepatitis C treatments) and, if you rely on public insurance, whatever bureaucratic processes are influencing time-to-approval. The Fraser Institute’s annual Access Delayed, Access Denied report (2012), recommended two policy alternatives to ameliorate these issues, including replacing public formularies with cash vouchers to subsidize the cost of private insurance. While CTAC fundamentally rejects such a proposal, we do see potential value in their other alternative, namely to recognize drug approval standards common with other jurisdictions and, in so doing, “speed up access to new drugs by harmonizing with European and American regulatory processes through mutual recognition of drug-approval decisions.”55 Such a proposal should be approached with caution, as it is important to ensure international safety standards are in compliance with those currently employed by Health Canada, and that patient groups are ensured a crucial role in informing drug approval processes. Nevertheless, CTAC asserts that the CDR ought to remain focused on cost-effectiveness assessments alone, not on continuing to repeat Health Canada’s safety and efficacy assessments conducted prior to issuing its NOC.56

BOCEPREVIR AND TELAPREVIR: LESSONS LEARNED

Overall, compared to the median time-to-approval rates analyzed by the Gamble study, provincial formularies (and Non-Insured Health Benefits) listed boceprevir and telaprevir rather quickly. With a few notable exceptions, the maximum time difference between CDR recommendation and formulary listing was 1 year, 7 days for boceprevir and 1 year, 21 days for telaprevir. One outlier in this process was Ontario, which approved boceprevir unusually quickly, only 29 days after its CDR recommendation. However, without explanation, Ontario broke with all other formularies and, after waiting more than a year, listed telaprevir for use only with previous null responders. As of this writing, boceprevir and telaprevir have not been listed on the Yukon formulary, the Prince Edward Island formulary or the Newfoundland and Labrador formulary. In addition, telaprevir has not been listed on the Manitoba formulary.

Delayed clinical trial inclusion of people living with HIV/HCV co-infection did bear direct impact on the delayed listing of boceprevir and telaprevir for use with co-infected people. The initial CDR indications for boceprevir and telaprevir both recommend against providing the medications to people living with HIV/HCV co-infection, noting patients with HIV/HCV co-infection were excluded from clinical trials. Consequently, all formularies contraindicated the use of boceprevir and telaprevir among co-infected people, with one exception. The Alberta formulary elected to remain silent on HIV/HCV


co-infection in its listing, opening the door for doctors to review current available evidence and remain free to provide patients with the treatment they deemed most suitable, prescribing boceprevir or telaprevir as part of a triple-therapy.

In this case, the CDR’s recommendation against allowing people living with HIV/HCV co-infection to access boceprevir and telaprevir, propagated significant delays in treatment access, despite the availability of initial favourable evidence at the time. While boceprevir and telaprevir have been available in Alberta for people living with HIV/HCV co-infection since November 1, 2012, the CDR waited two additional months before it decided to review its co-infection decision.

Only as of June 13, 2013, 18 months and 16 months after the CDR recommended boceprevir and telaprevir for use only in people living with HCV mono-infection, did the CDR reversed its initial indication against allowing access to people living with HIV/HCV co-infection. As of this writing, Alberta remains the only formulary providing access to boceprevir and telaprevir for people living with HIV/HCV co-infection.

Delayed clinical trial inclusion of people

living with HIV/HCV co-infection did bear direct

impact on the delayed listing of boceprevir and

telaprevir for use with co-infected people.

22 CTAC

Table 2. Common Drug Review decisions and formulary listing dates for boceprevir and telaprevir.

FDA APPROVAL Submitted: November 10, 2010

Approved: May 13, 2011


Approved: May 23, 2011

HEALTH CANADA NOC Submitted: December 22, 2010

Granted: July 29, 2011


Granted: August 16, 2011

CDR RECOMMENDATION DATE

CDEC Meeting: September 21, 2011

Recommendation: October 24, 2011

CDEC Meeting: January 18, 2012

Recommendation: February 15, 2012

CDR RECOMMENDATION

List with Criteria:

a) At a reduced price

b) For use with people with detectable HCV in the last 6 months

c) For use with people with fibrosis levels 2-4

d) Not for use with people living with HIV/HCV co-infection

e) Use limited to one 44-week treatment57

List with Criteria:

a) At a substantially reduced price

b) For use with people with detectable HCV in the last 6 months

c) For use with people with fibrosis levels 2-4

d) Not for use with people living with HIV/HCV co-infection

e) Use limited to one 12-week treatment58

CDR REQUEST FOR ADVICE (FOR USE WITH PEOPLE LIVING WITH CO-INFECTION)


Recommendation: June 13, 2013

Suggests “under the direction of a physician experienced in” managing co-infected people, that boceprevir “may provide clinical benefit in this population where there is unmet therapeutic need.”59


Recommendation: June 13, 2013

Suggests “under the direction of a physician experienced in” managing co-infected people, that telaprevir “may provide clinical benefit in this population where there is unmet therapeutic need.”60

TIME DIFFERENCE IN APPROVAL (FOR MONO- VS. CO-INFECTED PEOPLE)

18 months 16 months

BOCEPREVIR TELAPREVIR


ALBERTA (AND NORTHWEST

TERRITORIES)

November 1, 2012 November 1, 2012

BRITISH COLUMBIA March 15, 2012 July 5, 2012

MANITOBA September 24, 2012 Not yet approved

NEW BRUNSWICK October 31, 2012 October 31, 2012

NEWFOUNDLAND AND LABRADOR Not yet approved Not yet approved

NOVA SCOTIA July 27, 2012 July 27, 2012

PRINCE EDWARD ISLAND Not yet approved Not yet approved

ONTARIO November 22, 2011 March 2, 2013 (Note: only for previous null responders)

QUÉBEC February 22, 2012 April 23, 2012

SASKATCHEWAN April 1, 2012 April 1, 2012

YUKON TERRITORY Not yet approved July 1, 2012

NON-INSURED HEALTH BENEFITS (AND

NUNAVUT)

July 1, 2012 July 1, 2012

BOCEPREVIR TELAPREVIR

Table 2. Common Drug Review decisions and formulary listing dates for boceprevir and telaprevir cont'd

FORMULARY APPROVALS


TREATMENT DELAYED IS TREATMENT DENIED: POLICY OPTIONS

On April 12, 2013 at the 22nd Annual Canadian Conference on HIV/AIDS Research (CAHR), Dr. Curtis Cooper and Dr. Mark Hull presented a near-final draft of the Canadian HIV/Hepatitis C Management and Treatment Guidelines. These guidelines, developed by a national group of physicians and pharmacists, synthesized the breadth of available evidence on hepatitis C management and treatment in people co-infected with HIV/HCV, concluding that co-infected patients should be treated with triple-therapy including boceprevir or telaprevir, adjusting HIV prescription practices in accordance with known drug-drug interactions. Developed and presented prior to when the CDR revised its recommendation to support the use of boceprevir and telaprevir for people living with HIV/HCV co-infection under the supervision of physicians experienced in HIV and hepatitis C management, there is clearly a disconnect between regulatory oversight and medical practice that is creating treatment access barriers for people living with HIV/HCV co-infection.

It is inevitable that people living with HIV/HCV co-infection will be treated with the new hepatitis C therapies currently under development. In reviewing the evidence presented in Table 1, there is no reasonable explanation for delaying clinical trials or making myopic regulatory decisions that threaten the health outcomes for people living with HIV/HCV co-infection. It is of paramount importance that we all come together and improve our policy, research and programmatic responses to focus on treatment equity for people living with HIV/HCV co-infection, ensuring that a functional cure for hepatitis C is not refused to people who are arbitrarily offered substandard care.

POLICY OPTIONS

Recommendation 1: Regulations and recommendations on hepatitis C drug development, co-led between scientists, civil society groups and the pharmaceutical industry, must be developed, adopted and enforced by regulatory agencies (including Health Canada and the United States Food and Drug Administration).

The clinical trials for sofosbuvir demonstrate that protocols including people living with HIV/HCV co-infection work and can even be improved. Strong hepatitis C drug development guidelines should encourage HIV drug-drug interaction studies upon conclusion of Phase 2b clinical trials and upon successful indication, immediate Phase 2 and Phase 3 studies with people living with HIV/HCV co-infection. Enforceable standards, ensuring people living with HIV/HCV co-infection do not get left behind, should be led by a coalition of scientists, civil society groups, industry leaders and regulatory agencies.

Recommendation 2: The Government of Canada’s Panel for Research Ethics is encouraged to review the ethics of excluding people who are “harder to treat” and people who use drugs in the Tri-Council Policy Statement on Ethical Conduct for Research Involving Humans, to identify these as “inappropriate exclusions,” and to develop pragmatic guidelines on including “harder to treat” people and people who use drugs in clinical trials.

As mentioned earlier, the Government of Canada’s Tri-Council Panel on Research Ethics has identified guidelines on inappropriate exclusions of women, children and the elderly from clinical trials. In the context of hepatitis C and HIV drug development, an opportunity exists for the Government of Canada to play a leadership role in

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systematically identifying good practices on conducting clinical trials with “harder to treat” people. Further, the Tri-Council Panel on Research Ethics has a leadership role to play in operationalizing the findings of this systemic review and including “harder to treat” people as groups that are inappropriate to exclude from clinical trials. Additionally, clinical trial data must be disaggregated to ensure it is possible to analyze data we currently have available.

Recommendation 3: The Canadian Agency for Drugs and Technology in Health (CADTH), in coalition with hepatitis C and HIV civil society groups, must develop Therapeutic Reviews outlining good treatment availability and prescription practices in the areas of hepatitis C, HIV and HIV/HCV co-infection.

Since 2009, the CADTH has conducted therapeutic reviews, which is “a review of the most recent evidence available in the public domain regarding a single drug, a drug class, or a drug category.”61 To date, CADTH has completed 4 reviews,62 but have yet to review hepatitis C or HIV treatments. In light of the substantial hepatitis C drug development is taking place, CTAC recommends CADTH develop therapeutic reviews for hepatitis C and HIV, engaging scientists and civil society groups to identify in advance, unmet treatment needs for people living with hepatitis C, HIV and HIV/HCV co-infection. A proactive stance can provide guidance to pharmaceutical developers as to what therapeutic developments are most needed in patient populations and, in turn, potentially streamline development and approval processes.

Recommendation 4: Instead of recommending against using new hepatitis C medications among people living

with HIV/HCV co-infection, the Canadian Drug Expert Committee (CDEC) is advised to issue guidance in accordance with the language used after boceprevir and telaprevir were reviewed: new medications may fulfill “unmet therapeutic need” and “the treatment of patients co-infected with HIV and HCV should be under the direction of a physician experienced in managing such patients.”

CTAC recommends the good practice of allowing physicians and patients the autonomy to decide which therapeutic option is most appropriate at a given time, especially in the context of hepatitis C treatment, which remains complex and arduous.

Recommendation 5: The CADTH is advised to explore expanding the CDR's equity focus, drawing on equity-oriented tools available through the World Health Organization’s (WHO) Collaborating Center for Knowledge Translation and Health Technology Assessment in Health Equity.

The WHO’s Collaborating Center for Knowledge Translation and Health Technology Assessment in Health Equity has analyzed various health technology assessment tools based on their capacity to assess equity and access.63 One practical first step that can be taken by the CDR can take is to immediately include a person living with HIV, person living with hepatitis C and/or a person living with HIV/HCV co-infection on the CDEC when assessing a new HIV or hepatitis C medication. The CDR is also advised to consider maximizing implementation through health delivery systems when assessing new medications, especially for health technologies that simplify dosing and adverse event profiles.


MOVING FORWARD

CTAC commits to acting on each of the five policy options above, and will initiate and/or continue dialogue with Health Canada, the Tri-Council Panel on Research Ethics, the CADTH, as well as with industry partners developing new hepatitis C treatments and provincial and federal formularies, to promote increased equity for people living with HIV/HCV co-infection to access treatment without delay.

ADDITIONAL RESOURCES

The Canadian HIV/Hepatitis C Management and Treatment Guidelines are available online via the Canadian HIV Trials Network (CTN): http://www.hivnet.ubc.ca/2013/03/hiv_hcv/

The Sitges Statement on Hepatitis C Drug Development is available online: http://www.treatmentactiongroup.org/tagline/2007/september/sitges-statement-hcv-drug-development

Each of the clinical trials analyzed in this position paper can be explored further by going to http://www.clinicaltrials.gov and inputting the clinical trial registration number indicated in the references by the letters “NCT” followed by an 8-digit number.

CDR recommendations are available online at: http://cadth.ca/en/products/cdr

For more on CTAC’s ongoing work in HIV/HCV co-infection, please visit us at http://www.ctac.ca

http://www.hivnet.ubc.ca/2013/03/hiv_hcv/

http://www.hivnet.ubc.ca/2013/03/hiv_hcv/

http://www.treatmentactiongroup.org/tagline/2007/september/sitges-statement-hcv-drug-development



http://www.clinicaltrials.gov

http://www.clinicaltrials.gov

http://cadth.ca/en/products/cdr

http://www.ctac.ca


1 Benzacar A (ed.) 2012 Pipeline Report. i-BASE and TAG. Available: http://www.pipelinereport.org/toc.

2 Remis RS. Modelling the incidence and prevalence of hepatitis C infection and its sequelae in Canada, Community Acquired Infections Division, Communicable Disease and Emergency Preparedness Branch, Public Health Agency of Canada. 2007.

3 Soriano et al., Care of patients with chronic hepatitis C and HIV co-infection AIDS 16(6): 813-828.

4 Thomas DL. The challenge of hepatitis C in the HIV-infected person. Annu Rev Med. 2008 (59):473-485.

5 Klein MB, Rollet K, Saeed S, et al. HIV and Hepatitis C virus co-infection in Canada: Challenges and opportunities for reducing preventable morbidity and mortality. HIV Med. In Press.

6 See Public Health Agency of Canada, Enhanced Surveillance of Risk Behaviours Among Injecting Drug Users in Canada (I-Track) (2006). Available: http://www.phac-aspc.gc.ca/i-track/sr-re-1/index-eng.php.

7 Calzavara L, Ramuscak N, Burchell AN, et al. Prevalence of HIV and hepatitis C virus infections among inmates of Ontario remand facilities. CMAJ. Jul 31 2007;177(3):257-261.

8 Zakaria D, Thompson JM, Jarvis A, Borgatta F. Summary of Emerging Findings from the 2007 National Inmate Infectious Diseases and Risk-Behaviours Survey. Correctional Service Canada, 2010.

9 Miller CL, Johnston C, Spittal PM, et al. Opportunities for prevention: hepatitis C prevalence and incidence in a cohort of young injection drug users. Hepatology Sep 2002;36(3):737-742.

10 Spittal PM, Pearce ME, Chavoshi N, et al. The Cedar Project: high incidence of HCV infections in a longitudinal study of young Aboriginal people who use drugs in two Canadian cities. BMC public health. 2012;12:632.

11 Clarke JG, Stein MD, Hanna L, Sobota M, Rich JD. Active and Former Injection Drug Users Report of HIV Risk Behaviors During Periods of Incarceration. Subst Abus. Dec 2001;22(4):209-216.

12 Milloy MJ, Wood E, Small W, et al. Incarceration experiences in a cohort of active injection drug users. Drug Alcohol Rev. Nov 2008;27(6):693-699.

13 Orsi MM, Brochu S. The place of syringe exchange programs in reducing harm in Canadian prisoners. Can J Public Health. Jan-Feb 2009;100(1):29-31.

14 This is particularly true in Saskatchewan, where annual rates of new HIV diagnoses has increased nearly 1000% since 2001, and where 75% of new diagnoses occur in indigenous people, with 90% also diagnosed with HIV/HCV co-infection. See Saskatchewan Ministry of Health. Saskatchewan HIV Strategy. 2012: http://www.health.gov.sk.ca/HIV-strategy-update.

15 Pharmacodynamic and pharmacokinetic studies analyze how medicines interact with patients’ bodies.

16 For example, Phase 4 trials for boceprevir and telaprevir were mandated by the United States Food and Drug Administration. These trials have revealed the challenging drug-drug interactions associated with some antiretrovirals and boceprevir, as well as the potentially fatal skin conditions associated with telaprevir.

17 To read CTAC’s position paper on a Post-Market Surveillance System for Canada, please visit http://www.ctac.ca.

18 For a more detailed description of clinical trial design, see DeMets, D., Friedman, L., and Furberg, C., (2010). Fundamentals of Clinical Trials. Springer 4th Edition.

19 Adams C, Brantner V (2006). "Estimating the cost of new drug development: is it really 802 million dollars?". Health Aff (Millwood) 25 (2): 420–8.

REFERENCES

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20 Adams, CP, Brantner, V. Spending on new drug development. Health Economics 2010;19 (2): 130–141.

21 This analysis is a statistical technique to “clean up” data sets, excluding many patients who did not follow treatment protocol as prescribed by the trial.

22 For challenges associated with modified intention-to-treat analyses, please see Hollis S and Campbell F. What is meant by intention to treat analysis? Survey of published randomised controlled trials. BMJ 319 (7211): 670–674.

23 Dimova RB et al. Determinants of hepatitis C virus treatment and efficacy in drug users assessed by meta-analysis. Clin Infect Dis. 56 (6): 806-16.

24 Curcio F et al. Together... to take care: multidisciplinary management of hepatitis C virus treatment in randomly selected drug users with chronic hepatitis. J Addict Med. 4 (4): 223-32.

25 Grebely J et al. Optimizing assessment and treatment for hepatitis C virus infection in illicit drug users: a novel model incorporating multidisciplinary care and peer support. Eur J Gastroenterol Hepatol. 22 (3): 270-7.

26 Charlebois A et al. Factors associated with HCV antiviral treatment uptake among participants of a community-based HCV programme for marginalized patients. J of Viral Hepatitis 2012.

27 See Fairness and Equity in Research Representation, Panel on Research Ethics, Government of Canada, Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (2010). Available: http://www.ethics.gc.ca/eng/policy-politique/initiatives/tcps2-eptc2/chapter4-chapitre4/

28 The Sitges Statement is available at http://www.treatmentactiongroup.org/tagline/2007/september/sitges-statement-hcv-drug-development.

29 A rapporteur report from Sitges 2012 by le Collectif Hépatites Virales (in French) is available here: http://www.collectif-hepatites-virales.org/spip.php?article69.

30 Please note an observational Phase 2 trial of telaprevir is included here, the focus of which was to determine viral kinetics of triple-therapy with pegylated interferon, ribavirn and telaprevir. People enrolled in this trial were rolled into the Phase 2 trial described in Table 1.

31 NCT00160251: PEG-Intron/REBETOL vs PEG-Intron/ SCH 503034 With and Without Ribavirin in Chronic Hepatitis C Virus Genotype 1 (HCV-1) Peginterferon Alfa/Ribavirin Nonresponders: A SCH 503034 Dose-Finding Phase 2 Study. Available: http://clinicaltrials.gov/ct2/show/NCT00160251?term=boceprevir&phase=1&rank=1

32 NCT00262483: A Phase 2 Study of VX-950 in Combination With Peginterferon Alfa-2a (Pegasys®) and Ribavirin (Copegus®) in Subjects With Hepatitis C. Available: http://clinicaltrials.gov/ct2/show?term=telaprevir& phase=1&rank=20

33 NCT01188772: A Multi-center, Placebo-Controlled, Dose Ranging Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Following Oral Administration of PSI-7977 in Combination With Pegylated Interferon and Ribavirin in Treatment-Naïve Patients With Chronic HCV Infection Genotype 1, and an Open Label Assessment of PSI-7977 in Patients With HCV Genotypes 2 or 3. Available: http://clinicaltrials.gov/ ct2/show/NCT01188772?term=PSI-7977&phase=1&rank=4

34 NCT00423670: A Safety and Efficacy Study of SCH 503034 in Previously Untreated Subjects With Chronic Hepatitis C Infected With Genotype 1. Available: http://clinicaltrials.gov/ct2/show/NCT00423670? term=boceprevir&phase=1&rank=5

35 NCT00336479: A Phase 2 Study of VX-950 in Combination With Peginterferon Alfa-2a (Pegasys®), With Ribavirin (Copegus®) in Subjects With Genotype 1 Hepatitis C Who Have Not Received Prior Treatment. Available: http://clinicaltrials.gov/ct2/show/NCT00336479?term=telaprevir&phase=1&rank=13&submit_fld_opt=

36 NCT00705432: A Phase 3, Safety and Efficacy Study of Boceprevir in Previously Untreated Subjects With Chronic Hepatitis C Genotype 1. Available: http://clinicaltrials.gov/ct2/show/NCT00705432?term=boceprevir &phase=2&rank=1


37 NCT00627926: A Phase 3 Study of 2 Dose Regimens of Telaprevir in Combination With Peginterferon Alfa-2a (Pegasys®) and Ribavirin (Copegus®) in Treatment-Naive Subjects With Genotype 1 Chronic Hepatitis C. Available: http://clinicaltrials.gov/ct2/show/NCT00627926?term=telaprevir&phase=2&rank=11

38 NCT01641640: A Phase 3, Multicenter, Open-Label Study to Investigate the Efficacy and Safety of GS-7977 With Peginterferon Alfa 2a and Ribavirin for 12 Weeks in Treatment-Naïve Subjects With Chronic Genotype 1, 4, 5, or 6 HCV Infection. Available: http://clinicaltrials.gov/ct2/show/NCT01641640?term=GS-7977&phase=2&rank=3

39 NCT00708500: A Phase 3 Safety and Efficacy Study of Boceprevir in Subjects With Chronic Hepatitis C Genotype 1 Who Failed Prior Treatment With Peginterferon/Ribavirin. Available: http://clinicaltrials.gov/ct2/show/ NCT00708500?term=boceprevir&phase=2&rank=5

40 NCT00758043: A Randomized Study of Stopping Treatment at 24 Weeks or Continuing Treatment to 48 Weeks in Treatment-Naïve Subjects With Genotype 1 Chronic Hepatitis C Who Achieve an Extended Rapid Viral Response While Receiving Telaprevir, Peginterferon Alfa2a (Pegasys®) and Ribavirin (Copegus®). Available: http://clinicaltrials.gov/ct2/show/NCT00758043?term=telaprevir&phase=2&rank=12

41 NCT00959699: A Phase 2b, Safety and Efficacy Study of Boceprevir in Patients Coinfected With HIV and Hepatitis C (Protocol No. P05411). Available: http://clinicaltrials.gov/ct2/show/NCT00959699? term=boceprevir &cond=HIV&phase=1&rank=1

42 NCT00983853: A Phase 2a, 2-Part, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Study of Telaprevir in Combination With Peginterferon Alfa-2a (Pegasys®) and Ribavirin (Copegus®) in Subjects Who Have Chronic HCV-1/HIV-1 Co-Infection and Are Treatment-Naïve for Hepatitis C Available: http://clinicaltrials.gov/ct2/show/NCT00983853?term=telaprevir&cond=HIV&rank=2

43 NCT01565889: Part A: Drug Interaction Study Between GS-7977 and Antiretroviral Therapy (ARV) Combinations of Efavirenz, Tenofovir and Emtricitabine; Efavirenz, Zidovudine and Lamivudine; Atazanavir/Ritonavir, Tenofovir and Emtricitabine; Darunavir/Ritonavir, Tenofovir and Emtricitabine; Raltegravir, Tenofovir and Emtricitabine in Human Immunodeficiency Virus and Hepatitis C Virus (HIV/HCV) Co-infected Patients. Part B: A Phase 2, Open-Label Study to Investigate the Efficacy and Safety of GS-7977 With Peginterferon Alfa 2a and Ribavirin for 12 Weeks in Treatment-Naïve HIV/HCV Co-infected Patients. Available: http://clinicaltrials.gov/ct2/show/ NCT01565889?term=GS-7977&rank=5

44 NCT01335529: Pilot Study to Assess the Efficacy and Safety of Boceprevir, in Combination With Peg-Interferon Alfa and Ribavirin, in Patients With HCV/HIV Co-infection Who Have Failed to a Previous Therapy With Peg-Interferon/Ribavirin. Available: http://clinicaltrials.gov/ct2/show/NCT01335529?term=boceprevir&cond=HIV &phase=1&rank=2

45 NCT01513941: Open-Label, Phase 3b Study to Determine Efficacy and Safety of Telaprevir, Pegylated-Interferon-alfa-2a and Ribavirin in Hepatitis C Virus Treatment-Naïve and Treatment-Experienced Subjects With Genotype 1 Chronic Hepatitis C and Human Immunodeficiency Virus Type 1 (HCV-1/HIV-1) Coinfection. Available: http://clinicaltrials.gov/ct2/show/NCT01513941?term=telaprevir&cond=HIV&rank=5.

46 NCT01667731: A Phase 3, Open-label Study to Investigate the Efficacy and Safety of GS-7977 Plus Ribavirin in Chronic Genotype 1, 2 and 3 Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV) Co-infected Subjects. Available: http://clinicaltrials.gov/ct2/show/NCT01667731?term=GS-7977&cond=HIV&phase=2&rank=1.

47 The FDA approval notice for boceprevir is available: http://www.fda.gov/ForConsumers/ByAudience/ ForPatientAdvocates/ucm255413.htm

48 The FDA approval notice for telaprevir is available: http://www.fda.gov/ForConsumers/ByAudience/ ForPatientAdvocates/ucm256328.htm

49 The FDA has granted sofosbuvir priority review status and anticipates a decision as of December 8, 2013. Gilead’s press release on the priority review is available: http://www.gilead.com/news/press-releases/2013/6/gilead-announces-us-fda-priority-review-designation-for-sofosbuvir-for-the-treatment-of-hepatitis-c

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50 The Health Canada Notice of Compliance and Summary Basis of Decision for boceprevir is available: http://www.hc-sc.gc.ca/dhp-mps/prodpharma/sbd-smd/drug-med/sbd_smd_2011_victrelis_141556-eng.php

51 The Health Canada Notice of Compliance and Summary Basis of Decision for telaprevir is available: http://www.hc-sc.gc.ca/dhp-mps/prodpharma/sbd-smd/drug-med/sbd_smd_2012_incivek_142482-eng.php

52 The only HIV medication that has received a “do not list” recommendation from the Common Drug Review has been tenofovir (Viread), which has nevertheless been approved and widely available as Truvada (co-formulated with FTC).

53 Gamble JM et al. Analysis of drug coverage before and after the implementation of Canada’s Common Drug Review. CMAJ 183(17) (November 22, 2011). E1259-1266.

54 Ibid.

55 Rovere M and Skinner J. Access Delayed, Access Denied. The Fraser Institute (2012). Available: http://www.fraserinstitute.org/uploadedFiles/fraser-ca/Content/research-news/research/publications/access-delayed-access-denied-2012.pdf

56 See, amongst others, In the Balance: a renewed vision for the Common Drug Review. Canadian Diabetes Association (2012). Available: http://www.diabetes.ca/documents/get-involved/18401-CDA_CDR_5.pdf.

57 The initial Common Drug Review recommendation for boceprevir is available: http://www.cadth.ca/media/cdr/ complete/cdr_complete_Victrelis_Oct-26-11.pdf

58 The initial Common Drug Review recommendation for telaprevir is available: http://www.cadth.ca/media/cdr/ complete/cdr_complete_Incivek_Feb-17-12_e.pdf

59 The updated Common Drug Review recommendation for boceprevir is available: http://www.cadth.ca/media/ cdr/complete/cdr_complete_SF0303-Victrelis-RFA_June-14-13.pdf

60 The updated Common Drug Review recommendation for telaprevir is available: http://www.cadth.ca/media/ cdr/complete/cdr_complete_Incivek%20RFA-SR0305-June-14-13.pdf

61 For more information, visit http://www.cadth.ca/en/products/therapeutic-reviews/about-therapeutic-reviews.

62 Reviews exist for Relapsing-Remitting Multiple Sclerosis, Antithrombotic Therapy for Patients with Atrial Fibrillation, New Oral Anticoagulants for the Prevention of Thromboembolic Events in Patients with Atrial Fibrillation, and Biologics for Rheumatoid Arthritis.

63 The toolkit is available: http://www.cgh.uottawa.ca/whocc/projects/eo_toolkit/index.htm

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