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The United States and Canada have enjoyed close relations and a friendly rivalry that has lasted for centuries, covering everything from sports and politics to music and international conflicts. One key area of difference is in how the respective countries approve and regulate their prescription drugs. This affects not only the distribution of legal medication, but also how the drugs are abused and how the abuse is treated, revealing deep similarities (and more differences) in the special North American connection.

Prescription Drugs in the United States

In the United States, the process for the U.S. Food and Drug Administration approving a prescription drug for the consumer market begins with preclinical testing. The Journal of the American Board of Family Practice explains that a manufacturer gets things rolling by filing an investigational new drug application with the FDA. If the FDA approves the application, clinical trials begin, looking at the safety and pharmacology of the proposed drug. This is known as Phase 1. Phase 2 follows with studies that examine the effectiveness of the chemical compound. Phase 3 is the last step before the manufacturer submits an actual new drug application (known as an NDA at this stage) to the FDA. The application has all the information that the manufacturer obtained during the previous testing phases. Assuming approval by the FDA, the process moves to Phase 4, postmarketing studies.[1] As Perspectives in Clinical Research puts it, Phase 4 could be considered the first time that the drug is tested in real-world conditions as opposed to in purely clinical and controlled environments.[2]

Expanding on the details provided by the Journal of the American Board of Family Physicians, Medscape writes that preclinical phase usually takes about three or four years, and each of the first three phases takes roughly one, two, or three respective years to complete. Overall, the entire process of prescription drug approval can take as long as 12 years, during which time the FDA and the scientists leading the trials are in constant communication about safety and procedures. The FDA has the authority to approve a new drug application, reject it, or request further study from the manufacturer in order to make a final decision. Upon acceptance, the FDA can also request that the manufacturer initiate additional postmarketing studies.[3]

More on the US. & Prescription Drugs

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Prescription Drugs in Canada

Formed in 1996, Health Canada is the branch of the Canadian government that oversees matters of public health, including the drug approval process. Under Health Canada, the Health Products and Food Branch (HPFB) is the authority that regulates and monitors the safety, effectiveness, and quality of medicinal products across the country, such as prescription drugs.[8]

As in the United States, clinical trials play a determining role in whether the Canadian government approves a prescription drug for sale. A manufacturer sends a clinical trial application to HPFB, requesting permission to distribute the drug to established and recognized investigators; the information includes results from preclinical tests, methods of production, information about dosage, and information regarding the investigators who will actually conduct the study.

If the clinical trial studies prove that the proposed compound has potential therapeutic value, and that this value is greater than the risks and side effects that the investigators document, the manufacturer can send a New Drug Submission to the Health Products and Food Branch of Health Canada. The information in this submission is derived from preclinical studies, any clinical studies done outside Canada, clinical studies conducted on similar drugs, details regarding the manufacturing of the drug, specifics on labeling and packaging, and any information on side effects and therapeutic claims.

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United States

The Cost of Approval

With dozens of layers of regulation, most chemical compounds (and the manufacturers behind those compounds) have an uphill battle to fight before approval is a reality. According to Occupational Medicine, only one compound makes it to marketing out of anywhere between 5,000 and 10,000 compounds selected for preclinical testing.[4]

In 1993, the Congressional Office of Technology Assessment put the cost of developing a new drug at $359 million, but more recent estimates place the amount at anywhere over a half-billion dollars to $1.8 billion or as much as $2.5 billion.[5]

The preclinical phase involves using recent developments made in understanding a disease or condition, and then combining those understandings with pharmacology, computer science, and chemistry in order to find a promising agent. Drug testing in living animals (usually rats) is the precursor to a clinical trial with human subjects, to demonstrate that the proposed medication will be safe for human consumption; for example, the FDA requires clarification that a chemical compound would not damage human chromosomes, and that the required dosage for effectiveness would not have toxic side effects. Assuming that the drug testing on rats yields satisfactory results, those results are offered in support of the investigational new drug application that the manufacturer sends to the FDA.

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It is only after the FDA accepts all this documentation that Phase 1 clinical trials can go ahead.[6]

The IND application also includes chemical and manufacturing information, pharmacology, and safety statistics, the reason for why the new compound should be used in clinical trials with human subjects, how the manufacturer will ensure the wellbeing of human volunteers, and an overall plan for clinical testing.

Drug Testing Phases

As required by the FDA, Phase 1 studies are centered on the safety and pharmacology of a submitted compound. This entails giving a small group of closely monitored and healthy volunteers low doses of the compound; when severe or life-threatening conditions are involved, the volunteers may be taken from people who already have the condition. Phase 1 trials usually involve between 20 and 100 volunteers, who are started off on low doses and then given gradually larger concentrations of the compound. Generally, 66 percent of the Phase 1 compounds will be determined to be safe enough for Phase 2 to commence.

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Phase 2 looks at how effective a compound is based on analysis of the smallest number of volunteers needed to provide enough statistical evidence to determine how effective a proposed drug is.

This could entail testing between 100 to 300 patients, all of whom suffer from the condition that the drug is intended to treat. For the FDA to grant approval (to Phase 3 and beyond), researchers will have to determine the effective dose of the drug, how it can be taken (intravenously or orally, for example), and how frequently the drug should be taken.

Phase 2 is the stage at which a substantial number of proposed drugs are discontinued because they turn out to be ineffective or because there are notable problems regarding safety or side effects.

Phase 3 is the final stage before a case is made to the FDA for approval. This is when researchers try to replicate their past findings, but this time in a larger population. As a result of this, studies that take place during Phase 3 can last anywhere from two years to an entire decade, involving thousands of patients across dozens of sites. The scope of Phase 3 studies are intended to demonstrate wide-scale safety and effectiveness, both in terms of the dosage and effectiveness of the compound. Phase 3 is another stage where potential drugs fail; even after undergoing intense inspection and scrutiny in the preceding phases, an estimated 10 percent of medications do not make it past the Phase 3 trials.

The Path to Marketing

When a drug makes it through Phase 3, a new drug application is submitted to the FDA. The NDA is made up of all the preclinical and clinical information derived from the various stages, such as the chemical composition and creation process, pharmacology and toxicity results, clinical trial results, and even the labeling that the manufacturer would like to have on their product. A new drug application to the FDA can also include experience with the medication from trials conducted outside the United States, as well as other studies related to the drug in question.

Upon receiving the new drug application, the FDA conducts its own independent review and then makes its recommendations. In 1992, the US Congress passed the Prescription Drug User Fee Act, which shortens the review time by allowing the FDA to collect user fees from pharmaceutical companies as a form of financial support to improve the review process.

The Act requires the FDA to review a standard NDA within 12 months of receiving it; “priority applications” are given an expedited timeline of six months. For drugs similar to those already on the market, the applications are considered standard; priority status is given to drugs that promise important advancements on existing pharmacological treatments.

As part of the review process, if the FDA feels that more information is needed or that the manufacturer needs to make any corrections, the agency issues a written request to that effect.

After all this, it is still possible for the FDA to reject the NDA. If this happens, the manufacturer is told why their drug was not selected for approval and how they could make a future application successful. Occasionally, the FDA will offer a tentative approval recommendation if the agency feels that only minor tweaks are needed before approval can be given (for example, if proposed labeling needs to be changed). It is only after the FDA approves a drug, that the compound can be marketed.

Once the review is complete, the NDA might be approved or rejected. If the drug is not approved, the applicant is given the reasons why and what information could be provided to make the application acceptable. Sometimes the FDA makes a tentative approval recommendation, requesting that a minor deficiency or labeling issue be corrected before final approval. Once a drug is approved, it can be marketed.[7]

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Canada

Risks and Benefits

When a New Drug Submission has been received, HPFB reviews all the included information, sometimes using outside consultants and independent advisory committees. HPFB looks at the safety and effectiveness of the drug, as presented in the data sent by the manufacturer, with an eye on the potential benefits and risks that the compound poses. The sponsor of the drug must also provide details on what it intends to give to healthcare practitioners and consumers, such as product brochures, promotional and educational material, etc.

If the Health Products and Food Branch makes the determination that the benefits of the compound are better than the risks, and that the risks can be minimized or controlled in some way, the drug is given a Notice of Compliance and a Drug Identification Number. With these, the manufacturer is allowed to market the drug in Canada, and the drug is recognized as having received official approval from Health Canada.

However, in the event that HPFB feels there is insufficient evidence to argue that the benefits of the drug outweigh the risks, the government can refuse to grant the sponsor the necessary marketing authorization to start producing the drug for consumption. If this happens, the manufacturer has the opportunity to present additional information or to resubmit its original submission at a later date with new supporting data. The manufacturer can also ask HPFB to reconsider its decision.

As with the Prescription Drug User Fee Act, the Health Products and Food Branch also allows for some drugs to be reviewed faster than other drugs. The Priority Review Process is intended for drugs that promise improved treatments for life-threatening or severely debilitating medical conditions, such as cancer or HIV/AIDS, because there is a scarcity of effective therapies that already exist.

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Government laboratories can test certain products even after they receive authorization to be sold, in order to further monitor the safety, quality, and effectiveness of prescription medication.

Monographs and Special Access

One area of difference between how the United States and Canada regulate their prescription drugs is the use (and lack thereof) of monographs. Health Canada explains that a monograph is a scientific standard, containing information about a particular product. Health Canada uses monographs to represent the government’s knowledge and experience about what is required for the proper, safe, and efficient use of the product at hand. Since Health Canada uses monographs, manufacturers are advised to use them if they want approval for their product to be marketed faster.

The Health Products and Food Branch also offers a Special Access Program for doctors to obtain access to drugs that are not currently authorized for distribution in Canada. This is intended for important pharmacological treatments to be made available before market approval. If the doctor makes the case that conventional therapies have failed, or will fail, specific patients, the Special Access Program may allow the doctor to prescribe an as-of-yet unapproved drug to those patients alone. HPFB will have to determine that the need for the drug is legitimate, and that the doctor requesting the special access is qualified to do so (and to treat those patients); only then will approval be granted. The drug’s manufacturer will also have to agree to release the compound to that doctor for the specific treatment as laid out in the Special Access Program application.

Recalls for Defective Drugs

After Health Canada approves a prescription drug for marketing, the government continues to regulate the product. The drug’s distributor is required to report any new information regarding (notable) side effects, including the failure of the drug to produce the expected therapeutic effect. The manufacturer also has to notify the Health Products and Food Branch about any new studies that may provide updated safety information and place a request for approval for any major changes to the drug. This can include alterations to the manufacturing process, the dosage amount and frequency, or other recommended uses for the drug.

Through HPFB, Health Canada conducts market research and monitoring, tracks reports of adverse reactions, and investigates complaints and problems reported by consumers and/or doctors and pharmacists. HPFB also provides licenses for most of the drug production facilities in Canada and conducts regular inspections as a condition for valid and up-to-date certification.

If recalls are necessary, it is HPFB’s responsibility to manage them. The National Post writes that the common defects reported were drugs that degraded before their expected expiration and contamination by microbes or other foreign substances.[9]

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BMJ Open reported that Health Canada has had to recall a “soaring” number of defective prescription drugs, from 42 in 2005 to 143 in 2013.

Canada’s Delayed Approval Process

Despite this, Health Canada’s drug approval process has come under fire for being much slower than its European and American counterparts. A report from the Fraser Institute noted that Health Canada takes almost a year to grant marketing approval for “safe and effective” prescription drugs while regulatory bodies in Europe and the United States are approved much faster. In 2010, for example, the average time for Health Canada to approve a prescription medication was 448 days; the European Medicines Agency took 319 days, and the American Food and Drug Administration took 299 days. For four years between 2007 and 2011, Health Canada took longer to approve new medicines than the FDA. The Fraser Institute’s report suggested that the Canadian government could align closer with international regulatory agencies if it wanted to improve its drug approval process.[10]


The Institute further warns that the abnormally long process “can add further delays for Canadians seeking treatment from these new medicines,” especially with how Canada’s individual provinces have their own jurisdictional standards for safety.[11]

The Journal of the Canadian Medical Association asks if the data that is required for drug approval in Canada “may be more onerous,” leading pharmaceutical manufacturers to delay their submissions until they feel that their applications have a necessary (but artificially inflated) chance of success with Health Canada (compared to the European Medicines Agency or the Food and Drug Administration). Furthermore, drug sponsors may hold back on submitting their applications to Health Canada because the value of receiving timely approval in Canada is relatively small when held up against the operational difficulties that could be caused if Health Canada requests additional information.[12]

The Journal of the Canadian Medical Association also posits that manufacturers have reduced opportunities to make submissions to Health Canada and choose to prioritize their drug approval submissions based on market profitability. Larger markets tend to draw the most submissions while small or niche markets might go unserved. Lastly, manufacturers may deliberately slow down their submissions to Health Canada because they have other drugs for which they want to obtain approval – drugs in high-priced markets that public health regulatory bodies in other countries might want to use as a point of reference.

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Health Canada and the FDA

The Canadian Medical Association Journal compared Health Canada to the FDA and wrote that the FDA offers programs that allow for the early submission of new drug compounds if manufacturers can make the case that the compounds will treat serious conditions for which there is no currently acceptable treatment. The programs are fast-track status and accelerated approval. Fast-track status provides a rolling review, whereby each module of the application is submitted as it is completed (as opposed to submitting all the application modules together). For cases granted fast-track status, the date of the first module’s submission is considered the date of submission for the entire application. Accelerated approval, on the other hand, lets manufacturers use surrogate outcomes that are not well established.

Both the fast-track and accelerated approval programs give drug manufacturers the freedom to submit effectively incomplete applications; Health Canada, on the other hand, offers no such flexibility. Health Canada is in the process of developing a program for orphan drugs, a pharmaceutical product that remains commercially undeveloped due to limited potential for market profitability. The Canadian government will consider the small size of a patient population to determine the development, evaluation, and ultimate approval of such orphan drugs.

The FDA programs, on the other hand, are already widely used for orphan drugs. The European Medicines Agency has had a similar program in place since 2004, whereby submissions for new drugs that address hitherto-unmet public health needs are accepted, even if the manufacturer making the submission has not yet provided comprehensive clinical data.

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The Contagion Effect

The CMAJ researchers compared the data of orphan drugs in Canada and the United States, expecting that orphan drugs in America “would have a relatively short submission day” compared to the reported submission delays in the European Union and Canada, which they expected to be similar. Overall, orphan drugs tend to be submitted much later in the process in Canada than in the EU and the US; the researchers discovered that many orphan drugs are never sent to Health Canada. For the drugs that are, the manufacturers try to send the submissions as soon as possible.

A significant factor in why the drug approval process in Canada can be as slow as it is, is because of the (perceived) risk of what happens if Health Canada requests additional information on the submission of a drug or requests for the results of new studies conducted on the safety, quality, and effectiveness of the drug. Such requests are thought to have a “contagion effect” on other public health regulatory bodies, which results in the approval process being slowed (or temporarily halted), which in turn causes pharmaceutical companies to hold off on submitting applications for their drugs in Canada until such time they have obtained approval for their drug from those other regulatory bodies.

Introducing a new drug to the market is expensive and takes considerable knowledge and experience in the regulatory process to be successful. Health Canada charges drug sponsors $341,770 (Canadian).[13] CMAJ notes that not all companies are capable of maneuvering through the regulatory submission process, which puts smaller drug manufacturers at a disadvantage, as they may not have dedicated Canadian staff with the necessary expertise; larger companies may not have this problem. The result of this is that smaller companies may choose not to submit certain applications for new drugs, preferring instead to target larger markets.

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Harmonized Systems

To address its problems with prescription drug approval, Health Canada has entered into dialogue with the Food and Drug Administration for the purposes of developing a “harmonized system” to receive and process new drug submissions. Drug manufacturers will be able to use the same electronic portal to submit their applications to both regulatory bodies with the idea that this will speed up the approval process. The system will also facilitate the approval of orphan drugs in Canada. The new portal allows manufacturers to submit drug approval applications to both Health Canada and the FDA, but there is no requirement that a manufacturer will have to make both submissions simultaneously. If the reason for delaying a submission for a new drug is because there is a lack of global regulatory capacity, the approval process itself does not have to be delayed. The Canadian Medical Association Journal posits that bringing Health Canada’s submission guidelines into harmony with those of the Food and Drug Administration “will accelerate the arrival of new drugs in Canada,” which will benefit smaller drug manufacturers that may be compelled to delay their submissions because of the hitherto lower capacity for getting new drugs approved.

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Prescription Abuse in the US and Canada

Another area where the Canadian and American public health organizations are working together is to combat the prescription medication epidemic. The crisis has ripped through both countries, striking every demographic and socioeconomic group. In Ontario, prescription medication – specifically opioid-based drugs – has killed almost 2,500 people in just three years. A drug safety researcher at Sunnybrook Health Sciences Centre told CityNews that the drug problem is Canada’s biggest public health problem, echoing similar sentiments south of the 49th parallel, the longest international border in the world between two countries.[14]

As a result of the abuse, expenses on treatment have increased nationally by 60 percent over four years; public programs spent $93 million on medications used to combat addiction to prescription painkillers in 2014, up from $57.3 million in 2011. Medical experts warn that the strain of fighting back against the epidemic is putting unprecedented amounts of pressure on Canada’s healthcare system to the point where federal and local governments “have failed to take adequate steps to stop doctors from indiscriminately prescribing highly addictive opioids to treat chronic pain,” in the words of the Globe and Mail. In 2015, doctors issued 53 prescriptions for opioid-based medications for every 100 Canadians.[15]

The scope of the crisis is comparable in the United States. The Centers for Disease Control explains that between 2000 and 2015, more than 500,000 people died from drug overdoses, which include a mix of prescription medication and illegal drugs, and the CDC explicitly points to prescription medication as a driver for drug-related fatalities. In 2015, opioids killed 33,000 people, on par with the number of people who died as a result of traffic accidents; nearly half of those 33,000 opioid deaths involved a prescription drug. An average of 91 people die every day as a result of an overdose.[16]

Staggering as the numbers are, they may represent only the tip of the iceberg. An April 2017 report from the CDC suggests that the prescription drug abuse crisis could be even more deadly than previously thought because some overdose-related deaths are caused by pneumonia and other infectious diseases. Coroners record these deaths based on the infectious symptoms, missing the prescription drug abuse that precipitated the infection. As a result of this, a number of drug-related deaths are not being counted as such, implying that the true toll of the crisis may be much higher than current figures reflect.

A CDC field officer told CBS News that in cases where a person dies of a “really profound infectious disease,” that cause of death may be the only thing written on the death certificate. When statewide programs survey coroners’ officers for prescription drug deaths, those cases are not included.[17]

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Heroin Maintenance

In the face of such overwhelming numbers, and a deeply entrenched public health epidemic, the Canadian and American governments are separately thinking outside the box. In August 2016, Prime Minister Justin Trudeau “quietly” signed legislation that would allow Canadian doctors to prescribe “pharmaceutical-grade heroin” to addicts who are resistant to all other forms of treatment. The Washington Post writes that this new law currently allows only one clinic, in Vancouver, British Columbia, to expand a program that lets heroin users shoot up in the controlled environment of a clinic. Such “heroin maintenance” programs have existed in a number of European countries for years, the idea being that this is the safest and most effective way to get chronic addicts into the sphere of treatment. The program sites are supervised by medical staff, on standby to intervene in the event of an overdose, and there is educational information and on-the-spot counseling on offer to addicts who are interested in receiving longer treatment.[18]

Past research, carried out by Canadian scientists, has suggested that heroin maintenance is an effective way to treat severe heroin dependence in addicts.[19] One such study, published in the New England Journal of Medicine, found that “[heroin] treatment and optimized methadone maintenance treatment resulted in high retention and response rates [among addicts]” while noting that given the nature of the problem, “there will continue to be a subgroup of patients” who will respond better to supervised heroin treatment than they would more standard methadone therapy. This may be the only way of getting those people into the healthcare system.[20]

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Worsening the Problem?

The Canadian government expects the prescription heroin program to be made available only in the places (and the cases) where “traditional options have been tried and proven ineffective.” Unsurprisingly, the planned program is not universally popular; the Conservative party of the Canadian Parliament stated that its preferred policy would be to take heroin out of addicts’ hands, not give it to them. The Hill accused Canada of giving up the fight against the drug crisis, saying that “[prescription heroin] is a setback to fighting the raging heroin epidemic in North America” because such a program condones drug use and eliminates the possibility and incentive of long-term recovery. The only outcome of this, says The Hill, is that Canada’s epidemic will only get worse.[21]

The United States has kept an eye on Canada’s foray into prescription heroin and safe injection sites for the people who have suffered the most under the prescription drug epidemic. Amid mounting criticism, Seattle, Washington, is poised to be the first city in the United States to receive public funding for its own safe injection program. Al Jazeera explains that Seattle’s program is in response to a record number of overdose deaths in King County, of which it is the county seat.[22]

One of the fastest-growing cities in the United States, Seattle is keen to ensure that its own opioid problem is kept away from public beaches and parks, where residents have complained that contaminated needles are often discarded by heroin addicts, many of whom got turned on to the deadly drug because of a prescription medication problem that got out of control. The Seattle Police Department commented to Al Jazeera that it would be “absolutely possible to establish [safe injection facilities] without harming public safety,” but many members of the public (especially those who live in King County, but outside the infamously progressive and liberal city of Seattle) object to their tax dollars being used to facilitate drug use and attract addicts with the (perceived) promise of free heroin.[23]

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Has Canada Made the Drug Crisis Worse?

For all the similarities that exist between the United States and Canada on how they regulate their prescription drugs and how they suffer from prescription drug abuse, the biggest public health crisis facing both North American nations might be the fault of just one of them. A blog on the Huffington Post explained that in 2010, the Food and Drug Administration ordered Purdue Pharma to reformulate OxyContin. Purdue Pharma is the manufacturer behind the OxyContin painkiller, the drug that is widely accepted to have jumpstarted the opioid epidemic. Pacific Standard says that the entire epidemic “was started by one pharmaceutical company,” for the way Purdue Pharma created a highly addictive brand version of the oxycodone compound, relentlessly marketed it to doctors and consumers, and then attempted to bury initial evidence of its most serious side effects and health risks.[24]

After fining Purdue Pharma $600 million, the FDA required the manufacturer to produce a new form of OxyContin that would be resistant to abuse attempts. Health Canada, however, imposed no such restrictions, despite pressure and pleading from American healthcare officials, federal lawmakers, state governors, and doctors. Instead, writes the Huffington Post, “the Canadian Department of Health has continued approving new generic forms of the old, abusable formula.”

Even after a bipartisan group of four senators and eight members of Congress (a group that included the entire Senate and House delegation from New Hampshire, a state that an official from the Drug Enforcement Administration called “ground zero” for the opioid crisis) officially requested that Canadian health officials ban the sale of the abusable form of oxycodone, generic forms of the drug are still sold (legally and illegally) in Canada, and they are smuggled over the country’s border with the United States.[25] Six years after the FDA outlawed the production and distribution of abusable oxycodone, the original form of the drug is still found in 49 out of 50 states.

“Americans have died as a direct consequence of Canada’s policy of deliberate inaction,” concludes the Post.[26] Canadians are paying their own price; in “an epidemic within an epidemic,” The Star writes that while Americans are the highest per-capita consumers of opioids in the world, Canadians come in second. Nonetheless, the International Narcotic Control Board notes that opioid abuse in the United States is showing the initial signs of declining; in Canada, however, “the numbers keep rising.”[27]

For all the centuries of close cooperation and ties between the two North American partners, the toll of the opioid epidemic, and the role each country has had to play in the birth and spread of the crisis, is a tragic chapter in their long story.

Citations

[1] “From Idea to Market: The Drug Approval Process”. (September-October 2001). Journal of the American Board of Family Physicians. Accessed April 26, 2017.

[2] “Phase IV of Drug Development.” (April-June 2010). Perspectives in Clinical Research. Accessed April 26, 2017.

[3] “From Idea to Market: The Drug Approval Process.” (2001). Medscape. Accessed April 26, 2017.

[4] “Occupational Health Issues in the Pharmaceutical Research and Development Process.” (January-March 1997). Occupational Medicine. Accessed April 27, 2017.

[5] “$2.6 Billion to Develop a Drug? New Estimate Makes Questionable Assumptions.” (November 2014). New York Times. Accessed April 27, 2017.

[6] “An Overview of the Pharmaceutical Industry.” (January-March 1997). Occupational Medicine. Accessed April 27, 2017.

[7] “FDA’s New Drug Evaluation Process: A General Overview.” (1992) Journal of Public Health Dentistry. Accessed April 27, 2017.

[8] “How Drugs Are Reviewed in Canada.” (December 2015). Health Canada. Accessed April 27, 2017.

[10] “Health Canada Drug Approval Process Slower than in Europe and US.” (June 2015). BC Medical Journal. Accessed April 28, 2017.

[11] Federal Delays in Approving New Medicines 2013.” (April 2013). Fraser Institute. Accessed April 28, 2017.

[12] “Delays in the Submission of New Drugs in Canada.” (January 2015). CMAJ. Accessed April 28, 2017.

[13] “Pharmaceutical Submission and Application Review.” (n.d.) Health Canada. Accessed April 28, 2017.

[16] “Understanding the Epidemic.” (December 2016.) Centers for Disease Control. Accessed April 29, 2017.

[17] “Deaths from Opioid Epidemic May Be Underestimated.” (April 2017). CBS News. Accessed April 29, 2017.

[18] “Canada Has Just Approved Prescription Heroin.” (September 2016). Washington Post. Accessed April 29, 2017.

[20] “Diacetylmorphine Versus Methadone for the Treatment of Opioid Addiction.” (2009). New England Journal of Medicine. Accessed April 29, 2017.

[21] “Canada Gives up on Addicts with Approval of Prescription Heroin.” (September 2016). The Hill. Accessed April 29, 2017.

[22] “Seattle Plans First Safe Drug-injection Sites in the US.” (April 2017). Al-Jazeera. Accessed April 28, 2017.

[23] “Initiative Would Ban ‘Safe Injection Sites’ in King County.” (April 2017). KING5. Accessed April 28, 2017.

[25] “DEA Official: NH ‘Ground Zero’ of Opioid Epidemic.” (October 2016). WMUR9. Accessed April 30, 2017.

[26] “This Canadian Drug Policy Is Killing Americans Too.” (March 2017). The Huffington Post. Accessed April 30, 2017.