10 Things You Should Know about Biologics and Biosimilars

I have been presenting on biologics and biosimilars for the last year and I have been surprised in the interest in the topic and how little many healthcare professionals know about these important medications. Here are 10 things that all healthcare professionals should know about biologics and biosimilars.

1.      Biologics Transformed Chronic Disease Management

For many conditions, such as rheumatoid arthritis (RA), inflammatory bowel disease, and plaque psoriasis the introduction of TNF-alpha’s and other immunomodulators transformed treatment. These products:

  • Reduce disability
  • Improve quality of life
  • Dramatic change in the health of patients

I was practicing in the pre-biologic era and saw how conditions such as RA led to incredible pain and disability for the vast majority of patients. The introduction of biologics provided patients with such hope that they could control their conditions.

2.      A Biologic is Grown and Not Synthesized

A biologic is not a chemically synthesized drug. It is manufactured from animals, or microorganisms, or through the use of, animals, or microorganisms. It not only includes monoclonal antibodies but also:

  • Insulin
  • Vaccines
  • Cytokines
  • Protein hormones
  • Gene therapy products

One of the easier ways to envision biologics, is they are closer to growing a crop in a farmer’s field than a reaction by mixing a number of chemicals. Biologics are typically grown, harvested, purified and modified. This is very different from making a drug like Aspirin® which can be done by combining the right chemicals in the lab.

3.      Biologics are Massive Molecules

The molecular weight Aspirin® is 180 Daltons.

The molecular weight of a small biologic like human insulin is 5,808 Daltons. When we look at monoclonal antibodies, they are 150,000 Daltons or almost 100,000 times the molecular weight of Aspirin®.  An easy an analogy is that the complexity of Aspirin® is like a skateboard, where a monoclonal antibody is like a jumbo airliner.

4.      Biologics are a Major Drug Cost Driver

From strictly a cost per day perspective, biologic therapies are costly compared to traditional medications. They significantly alter the course of many disease states and could lead to lower costs such as additional physician visits, hospitalization and complication management. It is important that we look at healthcare as a big pie and not the silos for drug, hospita, and professional services.

We also have to remember that the drugs have a major impact on the quality of life of individuals which is tough to attach a dollar figure to.

5.      The Biologic Market is Growing

The first biologic agents were just for a few conditions. Immunotherapy is a rapidly growing in the management of many conditions and is starting to be used much more frequently in oncology to target specific markers for various cancer types.3

We are going to see an ever-increasing number of specialty drugs that will be marketed for a handful of your patients.

6.      Biosimilars are Here to Stay

Several biosimilars have been launched in Canada. A biosimilar is defined by Health Canada as:

  • “A biologic drug that obtains market authorization subsequent to a version previously authorized in Canada, and with demonstrated similarity to a reference biologic drug. A biosimilar relies in part on prior information regarding safety, efficacy and effectiveness that is deemed relevant due to the demonstration of similarity to the reference biologic drug and which influences the amount and type of original data required. Biosimilar biologic drugs were previously referred to as Subsequent Entry Biologics.”

Some key things from this definition:

  1. They are similar but not identical to the refence biologic
  2. They rely on some of the safety and efficacy data from the reference biologic

7.      Biosimilars have a Different Approval Process than Generic Drugs

When a medication loses its patent protection another company is allowed to develop this medication. The approval of generic medications and biosimilars in Canada are very different.

For standard generics, there is no efficacy or safety trials required for approval. Typically, one strength of the generic drug is pharmacologically tested in small group of healthy volunteers. The max blood level (Cmax), time to maximum blood level (Tmax) and area under the concentration curve (AUC) must fall within a Health Canada specified range. If these parameters are within this range, the drug is approved for all of the indications of the reference drug.

Biosimilars are similar but NOT identical to the reference biologic. Health Canada requires the biosimilar company to test the efficacy of the biosimilar versus the reference biologic in patient groups that would be likely treated by the drug.  It is a trial that assesses for similar efficacy and safety as the originator.  If this occurs, the biosimilar may be approved for some or all of the indications of the reference biologic.

8.      Biosimilars are NOT Generic Biologics and NOT substitutable

As I have presented on the topic, many pharmacists are under the belief that when a biosimilar comes to market that all patients can be changed from the reference biologic to the biosimilar. This is not the case. Health Canada, the FDA and the EU do not endorse non-medical substitution.

Currently if a patient is on the reference biologic they should not be automatically changed the biosimilar.  The reverse is also true, and you should not go from the biosimilar to the reference biologic or another biosimilar.

9.      Extrapolation of Indication

One of the biggest issues with biosimilars for some clinicians is the extrapolation of indications. For example, the initial trials to approve one of the biosimilar infliximab were tested in patients with rheumatoid arthritis. This demonstrated a similar response and safety to the reference biologic.

The biosimilar was not tested in inflammatory bowel disease, but was given the indication even though they did not have trials to support its use in these populations.

That being said, the current data has not demonstrated an issue in using the biosimilar infliximab with these other indications.

10. Immunology with Biologics versus Biosimilars

Another concern that is raised with biosimilars is the potential increase in immunogenicity. The body can develop antibodies to biologics. When significant amount of antibodies form, treatment failure normally follows. There are concerns that the differences in the structure of the biosimilar can lead to an increase in immunogenicity. More information on this possible concern will become available as an increasing number of biosimilars come to market.

Everyone Working with Diabetes Should Have the FIT Injection Tool

I often present and develop lessons on the role of insulin in the management of diabetes.  One of the most significant barriers for many patients is the thought of injecting a medication into their body. In reality, this should not be a significant barrier as injecting with insulin pens and the ultra-fine pen needles causes minimal pain and discomfort. I usually tell patients that the pain from a insulin needle is usually less than an SMBG testing lancet.

Fit Forum for Injection Technique

One of my favourite tools to recommend when you have questions about injection technique for insulin and GLP-1 receptor agonists is the FIT Forum for Injection Technique.  Many of my CDE colleagues are familiar with this tool, but if you haven’t seen it, take a quick look.  It is worth downloading to have in case you have questions on injection technique.

Fit Technique Plus

The FIT Technique Plus section also provides some excellent healthcare professional and patient education tools on injection technique and needle selection.  These are highly practical and can be downloaded on demand when you are counselling a patient.

Download or Bookmark

I am not going to review all of their key recommendations.  If you ever have questions about injection technique for insulin or GLP-1 receptor agonists, this is likely the best starting point.  I suggest that you download it or bookmark it for when you need it.

 

Managing Chronic Pain (Tool)

New Tool for Chronic Pain Management

I have been writing about the management of chronic pain for close to a decade.  Although chronic pain occurs regularly in practice, many healthcare professionals are not sure of the best options to manage it.  Any time I present on the topic, I usually have a full room as colleagues.  Clinicians are always looking for the best treatments to manage many chronic pain conditions.  I was working on a program over the last week and I ran across a couple of tools developed by the Centre of Effective Practice that I think can help anyone manage chronic pain.

General Chronic Pain Assessment Tool

This tool is a great starting point.  It reviews many of the key steps to assessing a patient with pain. The tool covers the non-pharmacological options, the role of non-opioid medications and opioid medications.  It is a quick summary that should answer many of the common questions regarding the appropriate management of pain.  Like most of these tools, I encourage clinicians to download them.  You want to have them available when you are assessing a patient.

Appendix – My Favourite Part of Tool

As a pharmacist, my favourite part of this tool is the Appendix to the Management of Chronic Non Cancer Pain Tool. This tool summarizes the evidence for each of the interventions in chronic pain as well as the risk of harm.  It also provides the starting dosage, titration and adverse effects of both non-opioid and opioid treatments.  The drug table alone is worth downloading for any primary care clinician.

There is a good section in this tool that provides extensive key patient counselling points that any healthcare professional can integrate into a discussion regarding opioid therapy.

Although pharmacists were not the primary target group for this tool, I would recommend for every pharmacist to download it as it will help when counselling patients with chronic pain.

 

 

Travellers’ Diarrhea – What Can I Eat and Drink?

I present quite often on travel medicine and often get questions regarding the prevention and treatment of common travel-related conditions. I thought I would provide some background on travellers’ diarrhea as it is the most is the most predictable travel-related illness and occurs in a large number of travellers to resort destination .1

Travellers’ Diarrhea

The incidence rates of travellers’ diarrhea (TD) range from 20% to 90% for travel to low and middle-income countries (e.g. much of the Caribbean and Mexico).2 Attack rates range from 30% to 70% of travellers, depending on the destination and season of travel.1

Key Facts About Travellers’ Diarrhea

  • Mainly caused by the ingestion of contaminated food and beverages
  • Bacterial pathogens are responsible for most infections.
    • Bacteria account for 80-90% of TD1 with enterogenic Escherichia coli (ETEC) accounting for 1/3 of the cases from the Caribbean and Latin America2
  • Viral and protozoal infections account for the remaining 10-20% of TD cases1
  • Untreated bacterial TD usually lasts 3–7 days. Viral TD generally lasts 2–3 days.1
  • The risk of TD varies based on the region of travel. The world can be divided into three different TD risk categories:1
    • Low-risk countries include the United States, Canada, Australia, New Zealand, Japan, and countries in Northern and Western Europe
    • Intermediate-risk countries include those in Eastern Europe, South Africa, and some Caribbean islands
    • High-risk areas include most of Asia, the Middle East, Africa, Mexico, and Central and South America
  • Most travellers with TD will completely recover within a few days. Approximately 3% to 17% of patients with TD will develop post-infectious irritable bowel syndrome (PI-IBS).3

Did you know?

One bout of TD does not prevent future attacks. It is common to have >1 episode of TD during a single trip.1

Clinical Presentation

  • Travellers’ diarrhea symptoms not only include the passage of loose stools but commonly include:2
    • Nausea
    • Vomiting
    • Abdominal cramps or pain
    • Fever
    • Blood in stools (dysentery)

Changes in Classification of Travellers’ Diarrhea

In the past, severity of TD was determined by the number of bowel movements in a day. The 2017 International Society of Travel Medicine (ISTM) Guidelines for the prevention and treatment of travelers’ diarrhea: a graded expert panel report, recommended a change in classification from the number of bowel movements to the level of impairment caused by the TD.4 This classification was recommended as some patients with infrequent bowel movements (1-2 stools) with severe cramps and fever may be significantly more distressed than more frequent bowel movements without cramps or pain.4

ISTM Classification of Travellers’ Diarrhea4
Mild (acute) Diarrhea that is tolerable, is not distressing, and does not interfere with planned activities
Moderate (acute) Diarrhea that is distressing or interferes with planned activities
Severe Diarrhea that is incapacitating or completely prevents planned activities; all dysentery (passage of grossly bloody stools) is considered severe

NOTE: if there is significant blood in the stools, the traveller should seek medical care

Food and Beverage Recommendations for Travellers

The Travel Medicine: Expert Consult is a great reference for all healthcare professionals interested in travel medicine. In the travellers’ diarrhea chapter they have some excellent food and beverage recommendations.

Food, Beverage and Setting Recommendations for Travellers5
Category Safest choice Probably safe Unsafe
Food Hot, thoroughly grilled, boiled

Processed and packaged

Cooked vegetables and peeled fruits

Dry items

Hyperosmolar items (jams, syrup)

Washed vegetables and fruits (if washed in potable water)

Salads

Sauces and salsas

Uncooked seafood

Raw or poorly cooked meats

Unpeeled fruits

Fruit without a thick peel like berries

Unpasteurized dairy products

Cold desserts

Beverages Carbonated soft drinks

Carbonated water

Boiled water

Purified water (iodine or chlorine

Fresh citrus juices

Bottled water

Packaged ice (machine made)

Tap water

Chipped ice

Unpasteurized milk

Setting Recommended restaurants Local home Street vendors

Prevention and Treatment with Pharmacotherapy

I will cover the role of antibiotics, Dukoral®, bismuth subsalicylate, loperamide and probiotics in the prevention and prevention of TD in a future post.

References

  1. Connor B. Travelers’ Diarrhea – Chapter 2 – 2018 Yellow Book | Travelers’ Health | CDC. https://wwwnc.cdc.gov/travel/yellowbook/2018/the-pre-travel-consultation/travelers-diarrhea. Accessed June 26, 2017.
  2. Public Health Agency of Canada Government of Canada. Statement on Travellers Diarrhea. http://www.phac-aspc.gc.ca/tmp-pmv/catmat-ccmtmv/diarrhea-diarrhee-eng.php. Published April 31, 2015. Accessed December 10, 2017.
  3. Steffen R, Hill DR, DuPont HL. Traveler’s Diarrhea: A Clinical Review. JAMA. 2015;313(1):71. doi:10.1001/jama.2014.17006.
  4. Riddle MS, Connor BA, Beeching NJ, et al. Guidelines for the prevention and treatment of travelers’ diarrhea: a graded expert panel report. J Travel Med. 2017;24(suppl_1):S63-S80. doi:10.1093/jtm/tax026.
  5. Ericsson CD. Chapter 17 – Prevention of Travelers’ Diarrhea. In: Keystone JS, Kozarsky PE, Freedman DO, Nothdurft HD, Connor BA, eds. Travel Medicine (Second Edition). Edinburgh: Mosby; 2008:191-196.

 

Why Will Medical Cannabis be More Restrictive than Recreational Cannabis?

I read through the Government of Canada’s Proposed Approach to the Regulation of Cannabis.  I would encourage every person currently working with or are interested in working with cannabis to give it a read. 

My biggest concern was the Cannabis for Medical Purposes Section. Under this section, the current method of distributing medical cannabis by an authorization from a physician or nurse practitioner and shipped from a licensed producer stays intact when legalization of recreational cannabis occurs in July of this year. Although it is good news that medical cannabis is at least being discussed, I have several concerns with this decision.

1.    Recreational and Medical Users are Fundamentally Different

What bothers me the most about this document is the lumping of recreational and medical users as being the same. Their objectives from using cannabis are fundamentally different.  A recreational user tends to want a high THC and low CBD product to become altered (‘high’).  A medical user will commonly need a variable ratio of THC/CBD to manage the symptoms of their disease.

Saying that medical patients will have access through the recreational system is an issue.  First, they are lumped in with the recreational users. The options of cannabis products in the provincially authorized sellers have not been determined, but I would be surprised if it would be as extensive as what we have with the current medical system.

2.    Contrary to Popular Belief Cannabis is a Pharmaceutical Medication

When cannabis is ingested (either orally or through smoking/vaporization) it leads to pharmacological effects.  These can help to manage symptoms in a patient with chronic conditions but also help people without medical conditions to reduce stress, help them sleep or relax.

The use of cannabis in any patient with a medical condition can likely benefit with support and education from a healthcare professional with special training in cannabis.

3.    Some Medical Users Can’t Currently Access Cannabis

With the College of Family Physicians of Canada (CFPC) and different regulatory bodies coming out with strong positions against cannabis for medical purposes, many physicians will not authorize or refer patients for medical cannabis. When legalization of recreational cannabis occurs, many will wish to try cannabis but will not be provided any professional education on the cannabis strains that can best address their symptoms.

This could lead to patients with significant medical conditions accessing cannabis through recreational retailers.  I am worried that they will select cannabis types, administration methods that may not be the most appropriate.

4.    The Proposed Legislation Penalizes and Potentially Stigmatizes Medical Users

Under the proposed regulations, a recreational cannabis user can decide to purchase cannabis, walk into a government approved regulator and purchase the product the same day.  Under the medical system, a patient is authorized to receive cannabis, the authorization must be sent to a licensed producer, the form is verified, the patient orders cannabis and it is mailed to the patient.  This process can take at minimum days, and up to a couple of weeks.  This system and delay penalizes patients who need cannabis as a medical treatment.

If a medical cannabis user decides to buy his/her cannabis from an approved retailer.  They may first not carry the optimal strain for their medical condition or symptoms.  By purchasing cannabis at these retailers, they may also be stigmatized as just another recreational cannabis user.

Here is How I Feel Medical Cannabis Distribution can be Improved Starting in July:

  1. Allow other healthcare professionals with sufficient cannabis competencies to be able to authorize medical cannabis. Recreational cannabis will be a legal product, there should not be more restrictions on medical cannabis
  2. Acknowledge that medical cannabis users and recreational users are different and using cannabis for very different reasons
  3. Allow medical cannabis to be distributed directly by a healthcare professional. With cannabis being considered a pharmaceutical, it should be distributed through pharmacies like every other medication.  This ensures that every medical patient gets some counselling education regarding the benefits and risks of cannabis use
  4. Educate Canadians. Many seem to think that this drug is benign without any risk.  Medically complex patients should be provided education and support of a healthcare professional with cannabis training
  5. Develop cannabis competencies for healthcare professionals. This develops a standard of a care for medical cannabis users.  It also differentiates healthcare professionals with specialized cannabis skills

 

COPD Inhalers – Easy to Use Reference Tool

Choosing a COPD Inhaler

I was working on a COPD program over the last couple of weeks and came across a couple of great tools.

I have found that many clinicians and patients are often confused with all the different medications and inhaler options.  Resptrec has developed a couple of great tool for clinicians.  A great tool is the COPD medication chart.  It provides the different options for each of the main classes of COPD drugs in Canada (SABD, LAMA, LABA, ICS/LABA, LAMA/LABA).  It shows all the different devices for each class, as well as dosing and both the trade and drug names.

I like how this tool can be used with a patient in the device selection process when the product is being prescribed or can help to choose an alternative device in the class if they are having issues with an inhaler.  This may improve medication delivery and adherence.

It is just a great tool to download, have it available when you need to discuss the different COPD inhaler and medication options.

The tool can be downloaded from the Saskatchewan Lung Association at the RESPTREC resources page.

PS – They also have one of these tools for asthma medications as well.

Managing Atopic Dermatitis – Tools

I wanted to share a couple of useful tools that The Eczema Society of Canada has developed for primary care clinicians.

Atopic Dermatitis: A Practical Guide to Management

The first is their “Atopic Dermatitis: A Practical Guide to Management”.  I found the guide a very easy read, with a focus on patient management versus providing detailed facts.  It provides a Canadian perspective on the management of AD.  This guide is not a guideline document and does not have the use of the GRADE system for evidence.  It provides clinicians with highly practical advice for the management of this common chronic condition. I would recommend that this guide is one of the references that clinicians should consider downloading and having it available to address common AD issues. This guide can be downloaded at: Atopic Dermatitis: A Practical Guide to Management

Topical Treatments for Atopic Dermatitis

The second tool is the topical treatment chart for AD.  We know that many parents and some clinicians have ‘steroid phobia’.  This guide provides clinicians with a review of the different topical steroid potencies, where they should be used and other key considerations.  I have found that with all the products on the market, it is easy for clinician to be unsure what is a mild, moderate, high and ultra-potency steroid.

Again this is a great tool to download to have on your computer to be able to access it when there are concerns on which topical product to use for a patients AD.  This guide can be downloaded at: Topical Treatments for Atopic Dermatitis

 

Cardiovascular Outcome Trials in Diabetes – Summary Article

I just finished the following review article reviewing the major cardiovascular outcome RCT’s with antihyperglycemics in type 2 diabetes.  With the sheer number of published trials, it can be difficult for clinicians to keep current.  Although a long read, the article provides a great perspective from top diabetes KOL’s on the studies published to date.  It includes a great summary of the key information from the main trials.

Major take-homes from the article:

  • Most of the trials published to date have used a 3-point composite major adverse cardiac event (MACE) primary outcome (CV death, nonfatal MI, and nonfatal stroke).
  • Trials have shown that insulins glargine and degludec, sitagliptin, alogliptin, saxagliptin, lixisenatide, and once-weekly exenatide have neutral effects on MACE outcomes, thereby supporting the use of these drugs when needed to improve glycemic control with the goal of limiting microvascular complications without increasing CV risk.
  • The evidence for CV benefit from empagliflozin, canagliflozin, liraglutide, and possibly semaglutide versus placebo, supplemented by data from other studies, already has prompted reconsideration of treatment guidelines and is likely to alter clinical practice and reduce CV events and deaths among people similar to those enrolled in these trials.
  • The positive effect of the tested drugs on kidney disease, itself a CV risk factor. For example, empagliflozin (HR 0.61 [95% CI 0.53–0.70], P < 0.001), canagliflozin (HR 0.60 [95% CI, 0.47–0.77], P < 0.0001), liraglutide (HR 0.78 [95% CI 0.67–0.92], P = 0.003), and semaglutide (HR 0.64 [95% CI 0.46–0.88], P = 0.005) all reduced progression of renal disease more than would be expected from the improvements in glucose and blood pressure provided by these drugs.
  • Although it is inherently inappropriate to compare results among trials because they are conducted in different populations, with different protocols, and at different sites, the numbers needed to treat (NNTs) to prevent a MACE occurrence in EMPA-REG OUTCOME (63 over 3.1 years), LEADER (53 over 3.8 years), and SUSTAIN-6 (44 over 2 years) were similar to those observed for widely recommended therapies to prevent CVD such as lipid lowering with statins, antihypertensive therapy, and aspirin.
  • There was a call for more long-term safety and innovative trial design to help reflect the broader population of patients with type 2 diabetes.

Overall, a good read for clinicians involved in the management of type 2 diabetes.  The article also has three Canadian key opinion leaders as authors (Hertzel C. Gerstein, Bernard Zinman,Lawrence A. Leiter).  For clinicians wanting to read more, it can be downloaded free of charge at the following link: