FDA Issued Draft Guidance for Industry for HIV drug "Human Immunodeficiency Virus-1 Infection: Developing Antiretroviral Drugs for Treatment"

In an effort to help the industry to understand the requirements and expectations for drug development, FDA started to issue the guidance on individual therapeutic area. Here are some examples of the therapeutic area specific guidances:

• 2007 "Chronic Obstructive PulmonaryDisease: Developing Drugsfor Treatment " 
• 2008 "Diabetes Mellitus: Developing Drugsand Therapeutic Biologics forTreatment and Prevention" 
• 2014 "Hospital-Acquired BacterialPneumonia and VentilatorAssociatedBacterial Pneumonia:Developing Drugs for Treatment" 
• 2014"Clinical Trial Endpoints for the Approval of Non-Small Cell Lung Cancer Drug and Biologics".

The latest therapeutic area specific guidance is on HIV drug development "Human Immunodeficiency Virus-1 Infection: Developing Antiretroviral Drugs for Treatment". The draft guidance provides the detail guidance from pharmacology, pre-clinical, to the clinical trials. It covers all aspects in clinical trial design and statistical analyses for HIV drug development. It also touched on the issues that statisticians are discussing:

Regarding the missing data and the data collection after patient discontinuation from the study treatment:

"There is no single optimal way to deal with missing data from clinical trials. Sponsors should make every attempt to limit loss of patients from the trial, and when the loss is unavoidable, collect information that can help explain the cause of the loss and the final status of the patient. Analyses excluding patients with missing data or other post-treatment outcomes are potentially biased because patients who do not complete the trial may differ substantially in both measured and unmeasured ways from patients who remain in the trial. The method of how missing data will be handled should be specified in the protocol or the SAP. A patient retention and follow-up plan should be included in the protocol providing details on how to minimize missing data and collect follow-up information."

Regarding the timing of Statistical Analysis Plan completion and contents of SAP:

"Before unblinding any phase 2b or phase 3 trial, sponsors should have in place a detailed finalized SAP. Although sponsors can update or modify an SAP as long as the trial remains blinded, sponsors should recognize that a detailed discussion may be needed concerning data access and appropriate firewalls for maintaining the integrity of the blind. If any major modification occurs, sponsors should discuss the modifications with the DAVP. Ideally, the SAP should be prepared at the time the protocol is made final, but we recognize that changes are sometimes made later, but before unblinding. The SAP should be considered as part of the protocol, and it can be either a section within the protocol (encouraged) or a separate document. The SAP should include:

• Details on endpoint ordering

• Analysis populations

• Structure of statistical hypotheses to be tested

• Statistical methods including the mathematical formulations

• Level of significance or alpha-level

• Alpha adjustments for multiple comparisons or interim analyses if applied

• Definition of visit window

• Handling of missing data

• Sensitivity analyses

It is important that the SAP prospectively identify any covariates that are to be used in the analysis. It is also important to choose covariates that are expected to strongly influence outcome."