Guidance for Industry: Chronic Obstructive Pulmonary Disease: Developing Drugs for Treatment

Theresa Seiverd
BW706-Blog 2
1. Name: Chronic Obstructive Pulmonary Disease (COPD): Developing Drugs for Treatment
2. Status: Draft Guidance
3. Release Date: November 2007
4. Link to Guidance: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071575.pdf
5. Target Audience: Pharmaceutical companies that design, plan, and sponsor clinical trials
6. Laws and regulations referenced:
21 CFR 300.50-Fixed-combination prescription drugs for humans
7. Summary:
COPD is characterized by the presence of air flow obstruction due to chronic bronchitis or emphysema. Therapies for COPD may cover a wide range of targets such as: improving airflow obstruction; providing symptom relief for a chronic cough or shortness of breath; reducing or preventing exacerbations; altering the disease progression; and modifying the lung structure.
One of the major goals of this guidance is to assist drug companies in the design of clinical trials for new molecular entities in the treatment of COPD. One of the first considerations when developing a clinical trial is to consider the spectrum of patients with COPD since a drug may benefit some patients and not others. Another important consideration is to consider the type of drug under development and its target therapy since this will have impact on the efficacy endpoints measured. The emphasis of this guidance is on the evaluation of efficacy parameters that are discussed in detail to provide the sponsor with many outcome measurements to consider when designing a clinical trial. The guidance groups the endpoints into 3 broad categories of descriptions.
The first category describes physiological assessments. The physiological assessments include the pulmonary function test to determine the extent of airflow obstruction. This assessment can be easily obtained with a spirometry test that measures forced expiratory volume in 1 second (FEV1). Exercise capacity is another common assessment that determines the reduced capacity for exercise due to airflow obstruction. It can be easily obtained by measuring the duration of activity on the treadmill or stationary bike.
The secondary category describes patient or evaluator outcome measures. These assessments include symptom scores, activity scales, and health-related quality of life instruments. Symptom scores were based on a patient’s own self assessment of their health status. The measure may be based on a categorical, visual, or numerical scale. The activity scales can be used as supportive measures to show efficacy of the drug since they are not always reliable and have limitations. For instance, the scales require patients to recall prior symptoms and make comparisons that is hard to measure and can be subjective.
The third category describes surrogate and biomarker endpoints. Surrogates and biomarkers can be used in consideration as supportive assessments of the drug’s mechanism of action. FEV1 that was described above can be used as a surrogate marker to obtain the status of the disease. One commonly used biomarker is the high resolution chest computed tomography to assess the lung tissue structure, to determine the disease state, or to show evidence of whether the lung tissue is functional.
For Phase 3 studies, primary and secondary endpoints need to be chosen based on the drug’s mechanism of action on the target therapy. For instance, if the target therapy of the drug is to improve airflow obstruction then the primary endpoint or assessment would be to compare pre‑dose and post-dose FEV1 measurements to show the beneficial effect with the drug over time.
8. Rationale: The rationale for putting out a guidance specific to COPD is to provide companies with a basis of the FDA’s (ie, the agency) expectations of primary and secondary endpoints that should be considered for a particular indication on the drug label when planning for pivotal Phase 3 studies. It is also important to design the study with the expected duration depending on the label claim that is being sought.
9. Resulting recommendation: The main considerations for this guidance are built around efficacy endpoints that need to be addressed when considering a drug’s specific indication (or claim) such as indicated below.
a. For the indication, improving airflow obstruction, if the drug being studied is a bronchodilator then the endpoint change in post-dose FEV1 should be evaluated. For non-bronchodilator’s, the change in pre-dose FEV1 should be considered.
b. For the indication, providing symptom relief, the endpoint should be clinically meaningful, and the magnitude should be clinically relevant.
c. For the indication, modifying or preventing exacerbations, the endpoint should be clinically meaningful for measuring exacerbations. For example, some measurements that can be considered for exacerbations are: duration, severity, delay in occurrence of an exacerbation, or reduction of frequency of an exacerbation.
d. For the indication, altering disease progression, the preferred efficacy endpoint that should be considered is the serial measurement of FEV1 over time.
e. For the indication, modifying lung structure, a radiological assessment of lung structure should be considered along with evidence that the regenerated lung tissue is beneficial and benefit’s patients. The latter part may involve a physiological assessment such as FEV1 to show evidence of improvement of airflow obstruction.
The duration of the study is important and also must be taken into consideration when planning the design of the study. Depending on the claim, the recommended study duration can range from 3 months to three years to show evidence of efficacy. Longer durations may be necessary to adequately address safety factors too. The number of studies recommended depends on the drug and claim that is being evaluated. Typically, 2 confirmatory studies are done for Phase 3 trials. For indications such as altering disease progression or modifying lung structure, 1 study may be acceptable provided the design is acceptable and results are clinically significant and robust. In order to demonstrate efficacy, the design of the study should include 1 primary endpoint and with more than 1 secondary endpoints. This should be considered up front in the design.
10. Impact: This guidance offers companies a roadmap on how to design their clinical trials to provide meaningful benefit for patients with COPD. Once the company has defined its therapeutic target, it will have a better understanding of the benefits or claims that may potentially be put on the label. With this knowledge, choosing the primary and secondary endpoints to evaluate becomes more clear, and the development of the Phase 3 clinical program can be further defined.