SAS Programming in Drug Development Process

Statistics/ SAS programming in Drug Development

Programmers and biostatisticians working in the clinical research industries have successfully used SAS for many years to transform data, generate safety and efficacy results, and submit data to FDA. SAS in Drug Development provides innovative capabilities to not only meet the historic needs of the industry, but to efficiently collaborate across trials, phases, therapeutic areas, departmental organizations and technologies, and ultimately get drugs, biologics and devices to market faster.

What is a Clinical Trial?

  • An Investigation of a new pharmaceutical product or a new chemical entity in order to find out the safety and efficacy of the drug. On an average it takes 12 years for a drug to be approved for marketing. A clinical trial is a research study to answer specific questions about vaccines or new therapies or new ways of using known treatments.

Drug Approval Process: Before Conducting Clinical Trials:

  • Before the company starts its program of running clinical trials, it has to prepare an Investigational New Drug (IND) Application with the FDA. The IND application must contain information in three broad areas:
    • Manufacturing Information This information is assessed to ensure that the company can adequately produce and supply consistent batches of the drug.
    • Animal Pharmacology and Toxicology Studies – Preclinical data to permit an assessment as to whether the product is reasonably safe for initial testing in humans.
    • Clinical Protocols and Investigator Information – Detailed protocols for proposed clinical studies to assess whether the initial-phase trials will expose subjects to unnecessary risks.
  • Pre-IND Meeting: Pharmaceutical Company meets with the FDA prior to submitting an IND.  At least 30 days prior to scheduled meeting, the IND applicant submits to FDA a meeting package consisting of
    • background information
    • list of questions grouped by type (Product, Preclinical, Clinical and Regulatory)

Drug Approval Process: Clinical Trials

     Types of Clinical Trials in Humans

  • Phase I: Phase 1 trials try to determine dosing, document how a drug is metabolized and excreted, and identify acute side effects.
          Subjects: Usually between 20 and 80 healthy volunteers
  • Phase 2: Phase 2 trials gather further safety data and preliminary evidence of the drug’s beneficial effects (efficacy), and develop and refine research methods for future trials with this drug. 

       Subjects: approximately 100-300 people who have the disease or condition that the product potentially could treat.

  • Phase 3: Phase 3 trials further test the product’s effectiveness, monitor side effects, and, in some cases, compare the product’s effects to a standard treatment, if one is already available. 

       Subjects: approximately 1,000-3,000 people with the disease.

  • Phase 4: Phase 4 trials are done after the drug is approved, either because the agency wants further information or because the pharmaceutical company wants to prove an advantage over a competitor
SAS in Drug Development Process

SAS in Drug Development Process

Drug Approval Process: Study Design

  • Controlled: If the drug is compared to another treatment, it is a controlled study; otherwise, uncontrolled
  • Open-label: uncontrolled, all subjects receive drug
  • Randomized: If subjects are randomly  assigned to receive treatment, it is a randomized study; otherwise, non-randomized
  • Crossover: Multiple treatments or treatment conditions are given to the same subject at different times, usually with a “washout” between treatments to avoid overlap of drug effects
  • Blinded: If the subject or investigator remains “blind” to which treatment is given, it is blinded
    • Single-blind: The investigator knows which treatment the subject is receiving, but the subject does not know
    • Double-blind: Both the investigator and subject do not know which treatment the subject is receiving
Drug Approval Process

Drug Approval Process

Drug Approval Process: Clinical Study Terminology

  • Trial: Same meaning as “study”
  • Indication: Condition the drug is intended to treat
  • Period : Timeframe during the study in which a distinct study-related activity takes place (i.e., Screening, Titration, Treatment)
  • Washout: A period of time between treatments to ensure no “carryover” drug effects of the previous treatment to the next
    • May apply to the start of the study (i.e., washout of prior medications)
    • Usually used in crossover studies between treatments
  • Treatment: Medication/therapy that is given to the subject
  • Therapy: Same meaning as “treatment”
  • Treatment group: The group to which the subject is assigned, that all receive the same treatment regimen
  • Treatment sequence: The order of treatments that a subject or group of subjects is assigned to receive
  • Comparator: Drug given to compare effects with the study medication
  • Placebo: Contains inactive ingredients (no drug)
    • Given to compare actual effects of study medication and/or comparators with the “placebo effect” (if the study is blinded)

Drug Approval Process: Timeline and Documents

Drug Development Process - Timeline & Documents

Drug Development Process – Timeline & Documents

Drug Approval Process: Where Do Statistics/Programming Come Into Play?

  • Drug Development Process - Timeline & Documents

    Drug Development Process – Timeline & Documents

    CRO: While drug developers are an essential aspect of clinical research, they may not have the experience or manpower to find patients, collect data and navigate the FDA approval process.  This is where “Contract Research Organizations” come in and provide outsourced support to the clinical research process by offering services and assistance in conducting clinical trials.

  • Protocol: Document that maps out what study procedures will be done, by whom, and why. May be amended before or during trial as issues occur or because of new information or requirements.
  • Statistical Analysis Plan (SAP): Document that specifies the analyses to be used to prove efficacy. May be amended before the blind is broken—NOT after.
  • Case Report Forms (CRFs): Paper or electronic forms to collect specific data during the trial.
  • Table Requirements: Instructions to the programmer on content and format of the data presentations: summary tables and listings of individual patient data.
  • Randomization schemes: A schedule used for determining allocation of subjects to treatment groups for randomized trials.
  • Sample size calculations: Calculations to determine the number of patients needed in a clinical trial based on variable of interest, desired power, effect size of clinical importance, standard deviation, and test used, and study design.
  • Tables, Listings, and Graphs (TLGs): The programmed output of the results of the clinical trial based on the protocol, table requirements, SAP, and CRFs.
  • Drug Development Process - Timeline & Documents

    Drug Development Process – Timeline & Documents

    Clinical Data Interchange Standards Consortium (CDISC): Standards created to support the acquisition, exchange, and submission of clinical research and metadata. Data submitted to the FDA is recommended to be in this format

    • SDTM = Study data tabulation model
    • ADaM = Analysis data model
    • ODM = Operational data model
Drug Development Process - Timeline & Documents

Drug Development Process – Timeline & Documents

  • Query Responses: Following submission of the NDA to the Agency, the FDA may have specific queries about the data that may require additional programming and/or statistical interpretation. These responses tend to require a rapid turnaround.
  • Drug Development Process - Timeline & Documents

    Drug Development Process – Timeline & Documents

    Post-hoc analyses: Analyses that are not part of the original SAP, but that may be of interest after reviewing the data following the unblinding of the study. Post-hoc analyses can also be used to support manuscripts, abstracts, posters, other publications, or marketing tools.

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