Special considerations in design of clinical trials for special disease conditions -

Asthma & bronchitis and Respiratory Disorders

Name of the Guide:Dr. Manju SharmaAssistant ProfessorDepartment of PharmacologyFaculty of Pharmacy, Hamdard UniversityNew Delhi, India

Prepared By:Dr. Pankaj Bablani1st Semester PhD Pharmaceutical Medicine(Batch 2014 -15)Hamdard UniversityNew Delhi, India

Respiratory Disorder

• Humans anatomical features of the respiratory system include airways, lungs, and the respiratory muscles. Molecules of oxygen and carbon dioxide are passively exchanged, by diffusion, between the gaseous external environment and the blood.

• This exchange process occurs in the alveolar region of the lungs.

• The respiratory system can be subdivided into an upper respiratory tract and a lower respiratory tract based on anatomical features.

– The Upper respiratory tract includes the nasal passages, pharynx and the larynx,

– The Lower respiratory tract is comprised of the trachea, the primary bronchi and lungs.

Disorders of the Respiratory System can be classified into

• Obstructive conditions (e.g., emphysema, bronchitis, asthma attacks)• Restrictive conditions (e.g., fibrosis, sarcoidosis, alveolar damage,

pleural effusion)• Vascular diseases (e.g., pulmonary edema, pulmonary embolism,

pulmonary hypertension)• Infectious, environmental and other "diseases" (e.g., pneumonia,

tuberculosis, asbestosis, particulate pollutants):

Coughing is of major importance, as it is the body's main method to remove dust, mucus, saliva, and other debris from the lungs. Inability to cough can lead to infection. Deep breathing exercises may help keep finer structures of the lungs clear from particulate matter, etc.

Common Respiratory Disorders Include:

• Chronic Obstructive Pulmonary Disease (COPD) - Irritation of the lungs can lead to asthma, emphysema, and chronic bronchitis and people can develop two or three of these together.

• Chronic Bronchitis - Any irritant reaching the bronchi and bronchioles will stimulate an increased secretion of mucus. In chronic bronchitis the air passages become clogged with mucus, and this leads to a persistent cough.

• Emphysema - The delicate walls of the alveoli break down, reducing the gas exchange area of the lungs. The condition develops slowly and is seldom a direct cause of death.

• Asthma - Periodic constriction of the bronchi and bronchioles makes it more difficult to breathe.

• Pneumonia - An infection of the alveoli. It can be caused by many kinds of both bacteria and viruses. Tissue fluids accumulate in the alveoli reducing the surface area exposed to air. If enough alveoli are affected, the patient may need supplemental oxygen.

Asthma

• Asthma is a chronic lung disease that obstructs airflow

• The obstruction is reversible

• It involves difficulty in breathing due to – Inflammation (swelling)– Mucus in the airways– Tightening of muscles around the airways

Symptoms

• Coughing

• Wheezing (Whistling sound)

• Shortness of breath

• Chest tightness

• Sneezing & runny nose

• Itchy and inflamed eyes

Asthma Major Triggers• Tobacco smoke

• Dust mites

• Cockroach allergens

• Indoor mold

• Wood smoke

• Formaldehyde

• Volatile organic compounds

• Air pollution

• Cold, damp, windy, stormy weather

• Sudden temperature changes

• Weeds, trees, grass

• Strenuous exercise

• Respiratory infections

• Common food allergies

Bronchitis

• Bronchitis is an inflammation of the main air passages to the lungs. • Most prevalent in winter• Generally part of an acute URI• It may develop after a common cold or other

viral infection of the nasopharynx, throat, or bronchi

• Often with secondary bacterial infection

Symptoms

1. Malaise/Discomfort

2. Chilliness

3. Slight fever

4. Backache and myalgia

5. Sore throat

6. Distressing cough (Usually signals onset of bronchitis)

7. Dry Cough followed by mucous production.

Chronic Obstructive -Pulmonary Disease (COPD)

• Serious lung disease that over time makes it hard to breathe

• It is an umbrella term used to diagnose people who have chronic bronchitis, emphysema, or a combination of both.– Emphysema– Chronic Bronchitis

• Blocked (obstructed) airways make it hard to get air in and out. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lungs to noxious particles and gases

The cardinal symptoms of COPD are Dyspnoea, Sputum production and Cough.

Sign & Symptoms• Chronic cough• Shortness of breath while doing everyday

activities (Dyspenea)• Frequent respiratory infections• Blueness of the lips or fingernail beds

(Cyanosis)• Fatigue • Producing a lot of mucus (Sputum)• Wheezing

Difference Between COPD and Asthma

• People with the chronic bronchitis form of COPD find it hard to breathe because their airways become swollen and filled with mucus. The same change occurs in people with asthma, but there it is triggered by, or factors in the environment that cause a reaction. The triggers could be cigarette smoke, pet’s hair/fur, dust, or other things.

• People with COPD tend to have milder versions of symptoms like shortness of breath even without the presence of any trigger, but when they are exposed to triggers, their symptoms can become even worse.

Treatments & Therapies Encourage smoking cessation. Pharmacological therapies Non-Pharmacological therapies The mainstays of drug therapy• Bronchodilators (primarily β2 agonists, anticholinergics and less often

Theophylline) • Mucolytics agents• Long-acting β2 agonists (LABA) • Long-acting muscarinic antagonists (LAMA)2• Inhaled corticosteroids (ICS)• Anti-inflammatory (PDE-4 inhibitors)• Triple therapy (i.e. LABA + ICS + an Anti-cholinergic) Supplemental therapies• Oxygen• Pulmonary Rehabilitation and Physiotherapy• Immunizations Nutrition Exercise

Difference Between COPD and Asthma

• Age of Onset: Youngsters and Adults – Asthma is mostly diagnosed in childhood, and most children who have asthma begin exhibiting symptoms at an early age. (As early as 5 years) where as COPD, usually don’t get diagnosed until the age of 40 or older. That’s because the condition is often brought on by years of smoking, and it’s the result of the slow progression of the disease

Designing clinical trial• Several types of drugs that can be

developed are• Drug intended to improve airflow obstruction• Provide symptom relief• Modify or prevent exacerbations• Alter the natural progression of the disease. • Modifying lung structure

Methods to assess efficacy

• Different types of drugs may be developed for respiratory diseases which may provide symptomatic relief through improvement of airway obstruction, which may modify or prevent exacerbations or which may modify the course of the disease or modify disease progression.

• Depending on the mechanism of action of the drug substance under evaluation, a complete characterisation of the effect of any therapy would require the inclusion of a number of different variables belonging to those domains expected to be affected by the study drug, because most treatments will produce benefits in more than one area.

Patient characteristics and selection of patients

• Diagnosis should be considered in any patient who has symptoms of cough, sputum

• Production or dyspnoea or a history of exposure to risk factors for the disease, particularly tobacco smoking.

• Persistent symptoms indicating airflow obstruction and is not fully reversible• FEV1/FVC less than 0.70 as per GOLD criteria (Chronic Obstructive Lung Disease)

or below the lower limit of normal (LLN) in patients over 60 yrs of age

• No alternative explanation for the symptoms and airflow obstruction

• Patients with other causes of chronic airflow limitation should be excluded • Asthma, cystic fibrosis, bronchiolitis obliterans and fibrosis due to tuberculosis

or very rarely α1-antityripsin deficiency should not be recruited

Patient selection

• Disease severity - Severity classified on the basis of airflow limitation, symptoms, risk of worsening.

• The most widely accepted classification of the spirometric severity is according to the Global Initiative for Chronic Obstructive Lung disease (GOLD).

• The GOLD classification is based on the degree of impairment of lung function and it recognises four stages:

• Stage I: mild, • Stage II: moderate, • Stage III: severe and • Stage IV: very severe.

• Baseline characteristics - demographic data, pre- and post-bronchodilator FEV1, reversibility of airflow limitation, dyspnoea scale, duration of disease, frequency, duration, severity and management of acute exacerbations etc

• Smoking history - current and/or past history of tobacco smokingTobacco exposure should be monitored carefully throughout clinical studies in all patients and changes in smoking status documented and reported.

Patient selection• Depending on the objective of the study controlled patients, partially

controlled or uncontrolled patients selected.

• Patients randomized to study treatments should be free from respiratory infection.

• For clinical studies to investigate the efficacy of specific immunotherapy the patients history of allergy and the causal allergen should be well-documented before study entry.

• It should be ensured that treatment arms are balanced according to important predictors of outcome.

• Standardization of clinical methodology is important. Patients should be adequately trained in respiratory function testing, inhaler technique, compliance and the use of diary cards.

Strategy and design of clinical trials

• Early studies– When a new chemical entity is being developed full

pharmacokinetic/pharmacodynamic documentationis required.• Pharmacodynamic studies

– The mechanism of action should be characterised and the selection of the relevant pharmacodynamic endpoints justified. First studies in man should provide preliminary safety data and should determine the dose range to be studied in the therapeutic programme.

• Pharmacokinetic studies– The pharmacokinetics of the product should be described and

absorption, bioavailability, distribution, metabolism and elimination characterised.

– For orally inhaled drugs the extent of systemic absorption due to pulmonary absorption and gastrointestinal absorption should be distinguished

Strategy and design of clinical trials• Therapeutic exploratory studies

– Specific dose response studies. Extrapolation from previous dose finding studies in related diseases such as asthma are only of limited value as there is no certainty that two separate respiratory diseases would respond in a similar way to the same dose.

• Therapeutic confirmatory trials– The selection of patients for confirmatory studies will depend on the type

of drug and its intended place in the treatment. Patients should always be treated in line with international clinical management recommendations.

• Blinding/Masking– Double blinding is preferred. When a double blind study is not possible

(e.g. some inhalers are difficult to blind), a three-arm study comparing the new drug with placebo (blinded comparison), and an active comparator in the third arm of the study (un-blinded comparison) as another control arm is preferred.

Dose selection

• Selection is based on the pharmacokinetic considerations and from earlier phase dose-ranging studies using a pharmacodynamic (PD) or clinical efficacy endpoint

• Is based on the benefit over risk assessment.

• If more than one dose is intended to be marketed, comparative assessment of efficacy and safety between the doses is conducted.

Dose duration

The duration of active treatment in the phase 3 studies that will support efficacy depends on the type of drug being developed, because different types of drugs will need different periods to show clinically meaningful effect.

Improving airflow obstruction: Should be at least 3 months for a bronchodilator drug and at least 6 months for a non-bronchodilator drug.

Symptom relief: Should be at least 6 months.

Modifying or preventing exacerbations: at least 1 year.

Altering disease progression: Should be at least 3 years. Modifying lung structure: The duration of treatment will vary depending on

the expected magnitude of clinically meaningful benefit, but likely will be several years in duration.

Longer durations of treatment may be needed to adequately assess safety of a drug

molecule.

Methods to assess efficacy• Lung function• Changes in spirometric parameters - FEV1 is the most

extensively used parameter

• FEV1 measured both pre- and post-bronchodilator, both at baseline and at repeated visits during each study treatment period

• Other measures of lung function include – Inspiratory capacity (IC) – Functional residual capacity (FRC)– Residual volume/totallung capacity (RV/TLC)– Forced vital capacity (FVC)

Study planned in special population• The high incidence of asthma in children makes it a target population of

special relevance.

• Diagnosis of asthma in early childhood is challenging and is based mainly on clinical judgment, assessment of symptoms and physical findings.

• Recommended to commence studies as soon as potential benefit has been shown in adults and certainly prior to authorization of the product in adults.

• A well defined population of children need to be studied in each age subset. • Under six years of age• 6-12 years of age• Over 12 years of age.

• References:1. http:// www.ema.europa.eu2. http://www.fda.gov/cder/guidance/index.htm

Thank You