Phase II
Whereas Phase I studies are typically performed in healthy volunteers, Phase II studies are often the first clinical trials in people with the disease. These studies typically focus on safety, but often include exploratory efficacy measures that are based upon a candidate drug’s mechanism of action. In addition to evaluating safety and assessing some efficacy endpoints, other goals of Phase II studies include determining optimal dose and dosing regimens and identification of contraindications. There are no regulatory requirements for conducting Phase II studies. However, they serve an important function by confirming proof-of-concept studies, helping to reduce risks to participants prior to larger Phase III studies, and can streamline future Phase III studies, e.g., by selecting a single dose level.
Initial Phase II studies are typically in adults. It is important to start with adults as they understand the risks associated with participation in a research study. Once enough safety data are obtained in adults, studies then proceed to children. Children of all ages may be enrolled simultaneously, but it is often customary to enroll children ages 12 to 17 years first, then 6-11 years, followed by 2-5 years, and finally under two years of age, if it is anticipated that a candidate drug will benefit patients in the youngest age groups. Phase II trials are often complex and may incorporate specialized outcome measures. These trials frequently are conducted at research centers that are expert in Phase II studies.
Phase II studies are often double-blind, and there are usually two general treatment groups: drug-treated vs. placebo-treated. While Phase II studies are primarily safety studies, they often include a dose ranging design in order to choose the best doses to be used in the next study. Phase II studies may be single ascending dose (SAD) or multiple ascending dose (MAD). In a SAD trial, subjects are randomized to placebo or a drug cohort. The first drug cohort gets 1 dose of the lowest dose of the drug or placebo. A review of the safety data for the first dose cohort by the data safety monitoring board (DSMB) will occur, and if the study is determined to be safe, enrollment in the next highest dose cohort will begin. This process will continue as long as each proceeding dose cohort is safe or until the study ends. A MAD study is similar to a SAD study, but instead of getting just one dose of the candidate drug, study participants will receive multiple doses of the same dose of drug or placebo over time before the next highest dose cohort is enrolled. The number of study subjects in a Phase II clinical trial is variable. A trial that employees a SAD design may have less than 20 subjects whereas a MAD design may enroll over 400 subjects. As the primary objective for Phase II studies is safety and tolerability, the outcome measures reflect that. Typical Phase II safety outcomes include but are not limited to subject diaries, subject quality of life questionnaires, adverse events, vital signs, safety laboratories (electrolytes, liver function tests, renal function tests, CBC with differential count, urinalysis), ECG, radiographic imaging, pulmonary function testing, and occurrence of pulmonary exacerbations. While many people consider measures of lung function, changes in quality of life questionnaires, and frequency or time to pulmonary exacerbations efficacy outcomes, in Phase II studies, they are often considered safety outcomes to ensure that the investigational product under evaluation does not cause an acute worsening of underlying disease. Most Phase II studies are of insufficient duration or power to evaluate these parameters as measures of efficacy. Lack of a positive efficacy signal in Phase II often does not stop the development of a candidate drug. However, demonstration of negative effects and safety concerns will stop the development. Occasionally investigators will sub-classify Phase II studies into Phase IIa and Phase IIb. Phase IIa studies are often shorter (4-8 weeks) smaller pilot studies that are dose ranging in nature and focus almost exclusively on safety and tolerability with some exploratory efficacy measures. Phase IIb studies are larger, often longer (12 to 24 weeks) studies that focus on both safety and efficacy. These studies are frequently used by study sponsors to support the efficacy of their candidate drug in seeking regulatory approval, and usually significantly more expensive. The results of Phase IIb studies are critical in determining whether a candidate drug should go on to a much larger, longer, and more expensive Phase III registration study. Therefore, the sites that conduct Phase II studies must be experts in clinical trials and produce data of the highest quality.
Proof-of-concept (POC) or proof-of principle studies bridge Phase I and Phase II dose ranging/safety studies. POC studies are typically small, short, biomarker-based studies. POC studies are designed to detect a signal in a disease-relevant mechanism or biomarker relevant to the disease. POC studies assess changes in biologic outcomes which would presumably translate into clinical benefit. A biomarker is defined as“a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic response to a therapeutic intervention” (20). With respect to efficacy biomarkers for both Phase II studies and POC studies, selection depends upon a candidate drug’s mechanism of action. A biomarker in a clinical trial of CFTR modulator likely would not be useful in a clinical trial of an anti-inflammatory drug. Biomarkers that have been used in the past based upon where in the pathophysiologic cascade a drug exerts its affect are given in the Table. POC studies provide preliminary data on clinically relevant endpoints. The stronger the link between the biomarker and a clinical endpoint, the more likely that biomarker can be used in later phase studies(21). Whereas the typical Phase II study includes a placebo group and a drug treatment group, this is not always the case with POC studies in which there might not be a placebo group. In the absence of a placebo group, POC studies are usually open label; end-of-treatment outcomes are compared to their pre-treatment values in this design. This reduces the number of subjects that need to be enrolled in the study as well as the duration of the study, thereby reducing the overall cost. These trials frequently are too small to provide significant data about the clinical efficacy of a candidate drug, and in fact, POC studies may not reach statistical significance for the targeted biomarkers. The question then becomes whether trends in the right direction for a panel of biomarkers provides enough information to make a decision to proceed to Phase II safety studies, particularly if the POC study is being used as a method to screen for the most promising candidates to move forward. It is entirely possible that a beneficial therapy might be discarded if it doesn’t show any trends in a small, quick POC study.
One example that illustrates the risk of POC studies is the low-hanging fruit project initiated in the early millennium. In this project, anti-inflammatory drugs methotrexate, hydroxychloroquine, pioglitazone, and simvastatin, which were approved for other non-CF pro-inflammatory diseases were evaluated in people with CF. In these studies, subjects provided induced sputum samples at the beginning and end of 1-month of treatment to determine if the drug impacted inflammatory markers in CF sputum. None of the drugs demonstrated statistically significant differences in any inflammatory marker when post-treatment values were compared to pre-treatment values. High-dose ibuprofen was also studied using a similar study design because it was the only currently recommended anti-inflammatory drug for CF(22). Although it was already used clinically to treat inflammation in CF, high-dose ibuprofen demonstrated only trends in changes in sputum neutrophils and a statistically significant decrease in sputum IL-6(23). One wonders - had anti-inflammatory drugs been screened by changes of inflammatory markers in induced sputum in the 1980s, would ibuprofen have moved forward to a clinical trial? This then leads to the concern that other potentially beneficial anti-inflammatory drugs may have been removed from consideration using this study design. It is likely that the study design for the low hanging fruit project was flawed for a variety of reasons: other than ibuprofen, the anti-inflammatory dose of each drug for CF was unknown, the study was underpowered to detect a difference in stable subjects, the study duration was too brief to detect a drug’s anti-inflammatory effect, and sputum measures were too variable. However, if the studies were larger and longer, the benefit of using sputum as a screening tool diminishes.