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PROPOSAL FOR ASTHMA RELIEF TREATMENT –  ‘WHEEZ-O' INHALER

 

B.Sc. in Pharmaceutical Science

GMP and Regulatory Affairs Group Project

November 28, 2018

ASCA Health Co.

Team Members: Ana Carvalho, Summer Morgan, Christabel Chai Sing Chze, Jingxing Yang

Table of Content

1.0 Abstract……………………………………………………………………………………………2

2.0 Introduction………………………………………………………………………………………..2

2.1 What is Asthma?..........................………...…………………...………………...........2

2.2 Signs and Symptoms...…………………………………….……………..…………….3

2.3 Diagnosis………..........................…………………...…………….………..…...…….3

2.4 Treatment Plan............................………...………………………..…...……………..3

3.0 Drug design……………………………………………………………………………………….4

4.0 Drug Delivery…………………………..……………………………………………..................4

5.0 Ethics………………………………………………………………………………………………5

6.0 Pre-Clinical Studies. …………………………………………………………………………….6

6.1. Species Choice…………………………………………………………………………7

6.2. Sample Size………………………………………………….………………...……….7

6.3. Study Design.……………………………………………….…………………………..7

7.0 IND………………………………………………………………….……………………………..7

8.0 Clinical Trials……………………………………………………………………………………..8

8.1. Phase I: ……………………………..………………………………….……………….9

8.2. Phase II: ………………………………………………...……………………….……...9

8.3. Phase III: ………………………………………………………………….…….….….10

8.4. Phase IV: ………………………………….….…….…………………………………11

9.0 NDA………………………...……………...….….………………………………….…………..11

10.0 Marketing Approval (MA) ……………………………….…………………….….………….12

11.0 References.………………………………………………………………………….….……..12

1.0. Abstract

Asthma is a disease that afflicts many people worldwide, it is especially common in Ireland, with 12.5% of the population afflicted. As a result of this, treatment and symptom suppression are extremely important. The purpose of this proposal will be to demonstrate a simple and effective way of providing such treatment through an easy to use medium, our new drug product - Wheez-O, a relief inhaler. Animal testing will be performed on a mix of dog and mice samples, and later testing will be performed on humans once the pre-clinical trials are completed. The results of these tests will indicate whether or not, firstly, that the medication delivery system works as intended, and secondly, that it works effectively and to as high a degree if not higher than competing medications. The results will also affect the course of progression for the drug product in the future.

2.0. Introduction

2.1. What is Asthma?

Asthma is a disease which affects the lungs. This disease works by causing repeated occurrences of wheezing, breathlessness, tightness of the chest, and coughing. Asthma can be controlled by the use of medications which halt the triggers that cause the above episodes (CDC 2018). Common triggers of this disease, asthma, are dust mites - microscopic bugs found in homes, outdoor air pollution - sources such as factories and cars, pets - furry coats, mould - caused by humidity and moisture in the air, bad weather - thunderstorms, some foods, fragrances, and strong emotions - hyperventilation (CDC 2012).

Asthma works by affecting the bronchi - they are small airways in the lungs, making them sensitive and causing them to react to things that would not normally be an irritant such as cold air, dust, etc. Asthma does this by causing the muscles of the bronchi to contract, making them narrow - this results in leaving little space for airflow in and out of the airways. The lining of the airways begin to swell and mucus is produced, which then clogs these passages. Breathing will then become difficult and the chest will therefore need to work harder to allow for breathing (Asthma Society of Ireland 2018).

Figure 2.1. Illustrating the condition of muscles around

the airway during an asthma attack (Asthma Society of

Ireland 2018).

2.2. Signs and Symptoms

Symptoms of asthma include but are not limited to - wheezing when exhaling, chest pains, shortness of breath and frequent coughing attacks. Asthma attacks and symptoms can occur in many ways, including during exercise, as a result of inhaling fumes or dusts, or it could be triggered by allergens in the air (CDC 2012).

Figure 2.2. Showing the effects that asthma has on the bronchi, causing a thick layer of mucous to obstruct these airflow passages (NIH 2014).

2.3. Diagnosis

To diagnose asthma, a doctor will begin asking a patient questions such as:

“does your family have a history of asthma?”, “How frequent do asthma symptoms appear?” and “Do you wheeze or cough after exercise?”.

The doctor might also perform a spirometry test which is a breathing test that measures lung functionality or a peak expiratory flow rate test which is measured over time (HSE 2018).

2.4. Treatment Plan

ASCA Health Co. plans to manufacture a relief medication to treat and relieve the symptoms of asthma. This product will be in the form of an inhaler. The medication will treat asthma, and open up the bronchi in the lungs during an asthma attack. The drug product will be marketed for public use (via doctor prescription) as ‘Wheez-O' in Ireland and Europe.

Figure 2.3. Showing the pathway of asthma

In the bronchi of the lungs (Kanehisa Laboratories 2013).

3.0. Drug Design

Wheez-O will be a pressurised inhaler that delivers salbutamol sulphate in an aerosol form, and delivers 100µg of the active ingredient, salbutamol, each use. Salbutamol is part of a group of medicines called bronchodilators. Wheez-O contains HFA-134a (excipient; 1,1,1,2-tetrafluroethane) and will not contain any chlorofluorocarbons (EMC 2015).

4.0. Drug Delivery

Salbutamol works by increasing the release of K+ and decreasing the free intracellular Ca2+ in the bronchi. The muscles aren't able to contract as easily under these conditions and the airway is cleared. Salbutamol works on β2-adrenoreceptors around the bronchi and stabilises the receptors in an activate state by binding to them. This produces more cAMP. Increased cAMP is the main trigger for the release of K+. Salbutamol travels around the body before being deactivated by the liver.  The salbutamol begins working between 5-10 minutes. R-salbutamol is able to form a hydrogen bond of Asn-293 and the chiral hydroxyl group. This makes R-salbutamol a β2 agonist. Serines 203,204 and 207, the methanol group and the phenyl hydroxyl group form a hydrogen-bonding network. Asp-113 is an important part of binding and all β2 agonists can make the bond between Asp-113 and a secondary amine at the end of the alkyl side chain. There are strong interactions between Trp-286 and Phe-290. The less effectively albuterol binds with the Phe and Trp, the less active the intracellular cascades are. Β2 receptors can be active or inactive. When inactive no cAMP is produced. A receptor becomes active when an α subunit swaps a GTP for a GDP and binds to the receptor. The α subunit removes phosphate group from the GTP and adenyl cyclase produces cAMP. The receptor then becomes inactive again. When the salbutamol binds to the receptor it causes a push towards the activate, causing more cAMP to be made and allowing the muscle to relax more.

cAMP activates the protein kinase A. it has not been fully established how K+ relaxes muscles but it could be due to the lowering of electrical potential which reduces Ca2+ channels that are responsible for muscle contraction. PKA phosphorylates the agonist-bound receptor and as a result it unbinds from Gs and binds to Gi. After salbutamol unbinds from the receptor it  flows into the circulatory system and dissolves in the blood. This takes approximately 1.5 - 2 hours. Once the salbutamol reaches the liver it becomes inactivate due to it being given a sulfo-group. The salbutamol is then excreted or metabolised (EMC 2015).

Figure 4.1. Showing the mechanism reaction of salbutamol as mentioned in part 4.0. Drug Delivery (EMC 2015).

5.0. Ethics

The clinical trials research for our proposed product, Wheez-O, will include all known ethical considerations.

It is not deemed completely necessary to carry out animal testing in the clinical trials stage of the pre-formulation of our drug product, Wheez-O. The testing of animals is usually a required step for clinical trials as a pre-test to actual human testing, or as an alternative method to avoid testing in humans completely. This is mainly due to ethical requirements which can deem testing in humans as unacceptable (llling 2006). In the case that the regulatory authorities request animal testing prior to human testing, it is only ethical and moral to ensure the upmost humane and proper care of all animals used in experimental testing, and to use every effort possible to use the lowest possible number of animals in the testing process. To adhere to the ethical requirements of animal testing the Three R's, described by Russell and Burch in 1959, were used as our guiding principles (Cunning 2018). To achieve this, Replacement, Reduction, and Refinement was considered. The Fund for the Replacement of Animals in Medical Experiments, or FRAME, have been developing and validating methods based on the “Three R's”. One current method for eliminating the use of animals in testing is by removing the use of redundant tests, although this does not completely remove the use of animals as other tests require their use. Another way to replace the need for animal testing would be to carry out exposure testing on humans. This is a voluntary testing process and therefore more desirable. In regards to the testing of animals for our product, Wheez-O, we can apply some of our tests to the same animals being used. This would greatly reduce the number of animals required for use in the testing of our product, Wheez-O, and allow us to obtain more information from the same number of animals (Illing 2006). To refine our tests we can carry out methods such as careful handling of the animals by trained professionals, high standards of living and housing units, the provision of toys if necessary, and the important use of anaesthesia and pain relief during any procedures being carried out. This would greatly reduce any suffering and improve the welfare of any animals used (HPRA 2014).

When the time comes for human trials, it is planned to use men, women, and children of all ages. We intend to reduce any risks that may occur during human clinical trials by excluding pregnant women from the testing process. All eligible, and voluntary, participants will sign confidentiality and consent forms. These forms will be explained in both verbal and written form, containing only the relevant information about the research experiment but will be adequate, comprehensive, and understandable for information. The patients will know everything they need to know before they consent to the trials. The consent will only be accepted by ASCA Health co. based upon the appreciation and understanding of all facts and implications of the testing by each individual participant. There will be clear inclusion for participants who cannot consent themselves, i.e. Minors, as to ensure the best results from our testing we intend to use young children in our human clinical trials, as mentioned on page 4, asthma can affect those of all ages but mostly occurs during childhood (NIH 2014).

We will submit an application for our proposed clinical trial protocol to an Independent Ethics Committee (IEC) to review and approve our intended research trials, for the human testing portion. They will ensure the protection of the rights, safety, and well-being of the human participants that will be involved in our study trials (Cunning 2018).

6.0. Pre-Clinical Studies

For our pre-clinical trials there are several factors that need to be investigated such as  safety, dosage range, dosage frequency, pharmacodynamics, pharmacokinetics, and efficacy of Wheez-O. Our drug will be administrated to two different types of animal to analyse these critical factors. It is first tested on animals to make sure the public is not exposed to any unnecessary risk. Once all critical factors have been analysed and the pre-clinical stage has been completed then, Wheez-O can be identified for all its chemical and physical properties.

6.1. Species Choice

The choice of species is very important, especially for asthma trials. With asthma it's difficult to choose a species as it is difficult to find  laboratory animals with symptoms that can be considered as asthma. The two species we have chosen are mice and dogs. Past research has shown that mice are the best species for showing allergic responses in the airways. They are a very popular choice as there's detailed understanding of their genetics. Dogs have been known to develop allergic responses to antigens in a similar way as humans (Zosky 2007). Both males and females with be used throughout the trials.

6.2. Sample Size

Mice: 100

Dogs: 10

As there are two animal models, mice will have a much larger sample size as they are cheaper. There is a very wide understanding of their genetics, and there are various commercial mouse specific probes available for studying allergic outcomes, which allows for large studies to be organised. Most importantly it would be unethical to use dogs in the bigger study as they are the larger than mice and would also be more expensive models (Cunning 2018).

6.3. Study Design

Our study design for Wheez-O will be randomized, dosage escalating, and placebo-controlled. A sample of 10 mice and 1 dog will be used as a placebo control, meaning they will not be administered with the actual drug . 30 mice and 3 dogs will be administered with the minimal dosage that will be intended for humans. 60 mice and 6 dogs will be separated into sample of 10 mice and 1 dog, each sample will receive a higher dosage than the last until the maximum tolerated dose is calculated. All models will be administered with this drug once a day. This study will be carried out over a period of two years. Within these two years, the animals will be treated with the best possible care, receiving food, drink and the best veterinary care available. When the two-year pre-clinical trial has been completed, all models will be examined. 1 rat from the placebo study, 5 rats and 1 dog from the minimal dose study and 5 rats and 1 dog from the dosage escalating study will be studied using an autopsy to examine the lungs and respiratory tract. The rest of the models will be examined in their daily routine, comparing each case study and observing the effects of increasing the dosage, using the placebo-controlled study as a negative control (Cunning 2018).

7.0. IND

Upon successful pre-clinical trial development for Wheez-O, the next step will be to apply to the Food and Drug Administration (FDA) to obtain an IND - Investigational New Drug application. The purpose of this IND application is to show that Wheez-O will not cause any unnecessary risks to volunteers involved in the clinical trial for our product. The IND will carry Wheez-O to the next stage - Clinical Trials. The function of this IND will be to reinforce the safeguard and further the production of Wheez-O. The IND application will supply a strategy for clinical trials, with information regarding regulations, consent, and every detail that the volunteers need to know regarding the trial. An approved IND application by the FDA will permit the drug to be transported to other countries for further testing and analysis (Cunning 2018). The application forms that are required for our application will be “FDA 1571” for IND applications, and “ FDA 1572” for  the statement from the investigator. The IND application can only be submitted by ASCA Health Co. by a qualified person such as a physician partnership of ours, manufacturer or corporation, and submitted electronically to the FDA for approval (FDA 2018).

8.0. Clinical Trials

The planned purpose of these clinical trials is to determine the effects of our therapeutic drug product, Wheez-O, on a range of patients of various ages, health levels, and separate genders (male and female). The aim of these trials will be to obtain data on the safety and efficacy of our drug product, Wheez-O, on humans - the targeted species. Our clinical trials will be ran through three phases, Phase I, Phase II, and Phase III, and will consist of two types of trials - Treatment trial, and Quality of life trial. These clinical trials will commence once approval has been granted by the HPRA and EMA regulatory authorities. Excellent and thorough planning is key to gaining regulatory approval. We will publish our findings to further medical knowledge on Wheez-O and asthma itself. We are adamant that the company will adhere to strict ethical rules and guidelines throughout the entire trial process (Cunning 2018).

Table 1.1. Displaying a sample flow sheet for our clinical trial consent form (Cunning 2018).

8.1. Phase I

This phase will be an introduction of the investigational drug, Wheez-O, into healthy volunteers in the trial. It will assess the pharmacological and toxicological properties of Wheez-O in the human body, establish the maximum tolerates dosage amount, and determine the route of administration - aiming for oral administration, dosage size, and the frequency of the dose (dependant on the severity of non-healthy/asthmatic patients). If the results we obtain from Wheez-O in Phase I are acceptable then we shall progress testing of Wheez-O to Phase II.

Objective of Phase I - To assess the absorption and metabolism, effects on the organs and tissues, and side effects (as dosage amount increases) of Wheez-O (Salbutamol) in the human body.

Duration - 1 year approximately.

Study Design - The design of Phase I will be randomised. Volunteers will be randomly assigned into either test/control groups. This will remove bias and provide statistically comparable groups.

Inclusion criteria;

1. Written and understood consent (parental/guardian consent for minors).

2. Males, females, and children aged 10 - 50 years.

3. Direct assessment of Wheez-O.

4. Minimal population of 20 - 80 healthy individual volunteers.

5. Assess safety of the Wheez-O.

6. Volunteers willing to adhere to schedules for administration of Wheez-O, clinical visits and screening processes.

7. Compassionate use.

8. Random assignment of volunteers

Exclusion Criteria;

1. Pregnant/Breastfeeding females.

2. Volunteers undergoing/participating in any other clinical trials.

3. Children below the age of 10 years.

(Cunning 2018).

8.2. Phase II

(Treatment Trial)

This phase will be an early, controlled, clinical study to determine the effectiveness of Wheez-O and its short-term safety in the human body. It will compare the use of Wheez-O in volunteers against a placebo drug. We plan to assess the efficacy of Wheez-O, i.e. its dosage and frequency, and the toxicity of Wheez-O in long term use. If the results we obtain from Wheez-O in Phase II are acceptable then we shall progress testing of Wheez-O to Phase III.

Objective of Phase II - To determine the effectiveness in treating asthma via administration of Wheez-O, the short-term side effects of volunteers with asthma, and the dosage range of Wheez-O.

Duration - 2 years approximately.

Study Design - The design of Phase II will be a Historical control study. Volunteers in this Phase will receive Wheez-O, where the results will be compared to the Phase I results.

Inclusion criteria;

1. Written and understood consent (parental/guardian consent for minors).

2. Males, females, and children aged 10 - 50 years.

3. Direct assessment of Wheez-O.

4. Minimum population of 100 to 500 maximum healthy and asthmatic individual volunteers.

5. Assess safety of the Wheez-O.

6. Volunteers willing to adhere to schedules for administration of Wheez-O, clinical visits and screening processes.

7. Treatment AND control groups (Asthmatic and healthy volunteers).

8. Compassionate use.

Exclusion criteria;

1. Pregnant/Breastfeeding females.

2. Volunteers undergoing/participating in any other clinical trials.

3. Children below the age of 10 years.

4. Random assignment of volunteers

(Cunning 2018).

8.3. Phase III:

(Quality of life Trial)

This phase will be a clinical study to gather any necessary, additional information about the effectiveness and safety of Wheez-O. We aim to evaluate the whole benefit versus risk relationship of Wheez-O. It is planned to assess Wheez-O in trial volunteers against a placebo drug. This will assess and determine the efficacy and safety in vast detail, and the potential of Wheez-O in routine clinical practices. If Phases I, II, and III are successful then we will be able to establish whether Wheez-O will gain market approval for general, public use or not.

Objective of Phase III - To determine the benefits and/or risks, least common and long-term side effects, and labelling information for packaging of Wheez-O.

Duration - 3 years minimum.

Study Design - The design of Phase III will be uncontrolled. We will have obtained the relevant data on asthmatics using Wheez-O to determine the rates of asthma attack (increase/decrease).

Inclusion criteria;

1. Written and understood consent (parental/guardian consent for minors).

2. Males, females, and children aged 10 - 50 years.

3. Direct assessment of Wheez-O.

4. Minimum population of 1000 to 5000 maximum asthmatic, individual volunteers.

5. Assess safety of the Wheez-O.

6. Volunteers willing to adhere to schedules for administration of Wheez-O, clinical visits and screening processes.

7. Treatment AND control groups (Asthmatic and healthy volunteers).

8. Compassionate use.

Exclusion criteria;

1. Pregnant/Breastfeeding females.

2. Volunteers undergoing/participating in any other clinical trials.

3. Children below the age of 10 years.

4. Random assignment of volunteers

(Cunning 2018).

8.4. Phase IV:

This phase will assess the long-term safety of Wheez-O. The regulatory authorities, HPRA and EMA may request further studies, trials, and monitoring after approving Wheez-O for marketing, so post-marketing studies may need to be carried out. Patient size can vary so is not yet determined but will be post Phases I, II, and III. Efficient and thorough studies need to be carried out by trained and competent employees of ASCA Health Co. if we are to avoid any long-term side effects being observed as this could cause us to lose our license for Wheez-O, causing it to be pulled from market. This phase is relevant as Wheez-O is aimed to be a relief treatment to improve the quality of life for asthmatics as asthma is currently an incurable disease, so treatment use will extend far longer than Phase III treatment will last.

Duration - Numerous years (TBC).

(Cunning 2018).

9.0. NDA

To gain the ability to market ASCA Health Co.'s new drug product, Wheez-O, in the USA, we must submit a New Drug Application (NDA) to the US Food and Drugs Administration (FDA). The NDA will only be filed upon completion of Phases I – III, and will include all of the information we gathered during pre-clinical and clinical trials of our investigational new drug (IND) product, Wheez-O. All specific detailed information about the product, Wheez-O, such as identity, physical and chemical characteristics, safety, efficacy, stability, toxicity, strength, composition, and bioavailability will be included in the NDA. The NDA we submit to the FDA will include beneficial information regarding our methods for testing, specifications for the manufacture of Wheez-O, about pharmacology and toxicology, and all details for processing and packaging of Wheez-O. The FDA reviewers will reach their key decisions from the sufficient information and data analysis we provide to them in our NDA. Early approval will not be possible to obtain for Wheez-O as our product does not treat a life threatening disease (Cunning 2018).

10.0. Marketing Authorisation (MA)

ASCA Health Co.'s main objective is to get Wheez-O an MA to market in Ireland and the EU (and also the U.S.A). As we want to market in both locations we can bypass the HPRA and apply for an MA directly through the EMA via a centralised procedure. EMA single MA is valid in all EU countries as well as EEA countries. The EMA does not take direct appraisals of drug dossiers so it forwards the application to the relevant, selected regulatory EU bodies to appraise. A committee for Human Medicinal Products (CHMP) will review our NDA, carrying out individual assessments of Wheez-O to determine its efficacy and safety as a whole. The committee will review and balance the risks and benefits of Wheez-O, and hopefully outweigh the risks. Inspections of manufacturing SOP's, QC's, labelling and packaging, and the manufacturing site will determine if they are all sufficient and conclude whether an MA will be authorised for Wheez-O. As our product is a therapeutic drug, an MA is essential for a centralised procedure for the EMA. The evaluation of Wheez-O by a scientific committee will take up to 210 days, including “clock stops”. At the end of this evaluation they will give an opinion on whether we can or cannot market Wheez-O in Ireland and the EU. This opinion will then be transferred to the European Commission (EC) who will grant the ultimate authority of granting MA's in the EU. Once our MA is granted we can legally begin to market Wheez-O in all EEA countries. The MA will be valid for 5 years from the date of its first issue and will be renewed if we wish to continue marketing Wheez-O. The renewal must be submitted to the relevant authority 3 months before its expiry. After the MA's approval the EMA/HPRA will monitor type and frequency of reported side effects of Wheez-O. They can recall our product if it does not keep up to standard or if side effects increase rapidly (Cunning 2018)

11.0. References

Asthma Society of Ireland. (2018). Asthma Basics: What is Asthma? [online]. Available from: https://www.asthma.ie/get-help/learn-about-asthma/asthma-basics/asthma-basics [accessed 7th November 2018]

CDC. (2018). Asthma [online]. Available from: https://www.cdc.gov/asthma/ [accessed 7th November 2018]

CDC. (2012). Asthma: Common Asthma Triggers [online]. Available from: https://www.cdc.gov/asthma/triggers.html [accessed 20th November 2018]

Cunning, N. (2018). Good Manufacturing Practice (GMP) & Regulatory Affairs: Clinical Trials 1 [online]. QUALS7010: GMP and Regulatory Affairs. Dundalk Institute of Technology, Department of Applied Sciences. Available from: https://2019-moodle.dkit.ie/course/view.php?id=857 [accessed 15th November 2018]

Cunning, N. (2018). Good Manufacturing Practice (GMP) & Regulatory Affairs: Clinical Trials 2 [online]. QUALS7010: GMP and Regulatory Affairs. Dundalk Institute of Technology, Department of Applied Sciences. Available from: https://2019-moodle.dkit.ie/course/view.php?id=857 [accessed 15th November 2018]

Cunning, N. (2018). Good Manufacturing Practice (GMP) & Regulatory Affairs: Clinical Trials 3 [online]. QUALS7010: GMP and Regulatory Affairs. Dundalk Institute of Technology, Department of Applied Sciences. Available from: https://2019-moodle.dkit.ie/course/view.php?id=857 [accessed 15th November 2018]

Cunning, N. (2018). Good Manufacturing Practice (GMP) & Regulatory Affairs: Clinical Trials 4 [online]. QUALS7010: GMP and Regulatory Affairs. Dundalk Institute of Technology, Department of Applied Sciences. Available from: https://2019-moodle.dkit.ie/course/view.php?id=857 [accessed 15th November 2018]

Cunning, N. (2018). Good Manufacturing Practice (GMP) & Regulatory Affairs: Regulatory Authorities FDA & EMA  [online]. QUALS7010: GMP and Regulatory Affairs. Dundalk Institute of Technology, Department of Applied Sciences. Available from: https://2019-moodle.dkit.ie/course/view.php?id=857 [accessed 23rd November 2018]

Cunning, N. (2018). Good Manufacturing Practice (GMP) & Regulatory Affairs: Pre-clinical Studies  [online]. QUALS7010: GMP and Regulatory Affairs. Dundalk Institute of Technology, Department of Applied Sciences. Available from: https://2019-moodle.dkit.ie/course/view.php?id=857 [accessed 20th November 2018]

Cunning, N. (2018). Good Manufacturing Practice (GMP) & Regulatory Affairs: Regulatory Authorities Health Products Regulatory Authority [online]. QUALS7010: GMP and Regulatory Affairs. Dundalk Institute of Technology, Department of Applied Sciences. Available from: https://2019-moodle.dkit.ie/course/view.php?id=857 [accessed 25th November 2018]

Cunning, N. (2018). Good Manufacturing Practice (GMP) & Regulatory Affairs: Research Ethics [online]. QUALS7010: GMP and Regulatory Affairs. Dundalk Institute of Technology, Department of Applied Sciences. Available from: https://2019-moodle.dkit.ie/course/view.php?id=857 [accessed 14th November 2018]

EMC. (2015). Ventolin Evohaler [online]. Available from: https://www.medicines.org.uk/emc/product/850/smpc?fbclid=IwAR2F7vwhcFYCw62dubKS2AkNzHaFpk-dWQ9Au0eWQTzPJZ8_tspVu2Jy_7Q [Accessed 24th November 2018]

HPRA. (2014). The 3Rs [online]. Available from: https://www.hpra.ie/homepage/veterinary/scientific-animal-protection/3r%27s [accessed 20TH November 2018]

HSE. (2018). About Asthma [online]. Available from: https://www.hse.ie/eng/health/hl/living/asthma/aboutasthma/?fbclid=IwAR0FxM3PpbnPz8zBQ_vx7r2pZEHa9eeoMBmZmM01mQZxpHb89bMA_dC0zKw [Accessed 24th November 2018]

Illing, P. (2006). Issue in Environmental Science and Technology: Alternatives to Animal Testing [online]. Cambridge: The Royal Society of Chemistry. Available from: https://books.google.ie/books?hl=en&lr=&id=1dPnLZ47fOAC&oi=fnd&pg=PA1&dq=alternatalte+to+animal+testing&ots=qCNqGiW3SU&sig=RI2R9wmP422kcxsvMA_fJQPM7pQ&redir_esc=y#v=onepage&q&f=false [accessed 20th November 2018]

Kanehisa Laboratories. (2013). Asthma - Homo sapiens (human) [online]. Available from: https://www.genome.jp/kegg-bin/show_pathway?hsa05310 [accessed 7th November 2018]

Zosky, G. (2007). Clinical and Experimental Allergies, Volume 37, Issue 7, Animal Models of Asthma [online]. Available from: https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2222.2007.02740.x [accessed 26th Nov 2018]

NIH. 2014. Asthma [image online]. Available from: https://www.nhlbi.nih.gov/health-topics/asthma [accessed 7th November 2018]

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U.S. FOOD & DRUG ADMINISTRATION. (2018). Investigator-Initiated Investigational New Drug (IND) Applications [online]. Available from: https://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/investigationalnewdrugindapplication/ucm343349.htm [accessed 15th November 2018]

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