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SAS Clinical Programming

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Introduction to Clinical Research

The process from discovering a new drug to registering it for marketing is very complex and lengthy. There are several people involved in the process of drug discovery and development includes scientists, clinicians, statisticians, data managers, and SAS programmers. It is estimated that, on average, a drug takes 10-12 years from initial research to reach the market. Drug discovery and development are mainly carried out by pharmaceutical companies and research agencies. The pharmaceutical market is very competitive. It is imperative that pharmaceutical companies discover and develop drugs efficiently and within the shortest time span to remain competitive.

Drug Development Process

The drug development process has different stages:

  • Drug Discovery
  • Drug Development
  • Clinical Trials
  • Manufacturing
  • Marketing approval

The Drug Discovery Process involves in finding out the target that causes the disease, chemical or biological compounds are screened and tested against these targets to find leading drug candidates for further development. The Drug Development Process involves Tests performed on the lead compounds in test tubes (laboratory, in vitro) and on animals (in vivo) to check how they affect the biological systems. The development Process includes pharmacological studies of the lead compound and its effects on toxicity, carcinogenicity, mutagenicity and reproductive development. These data are important for determining the safety and effectiveness of the lead compound as a potential drug. Typically, tens of thousands of compounds are screened and tested, and only a handful makes it into the market as drug products. The statistics are such that, of 5000 compounds that show initial promise, five will go into human clinical trials, and only one will become an approved drug.

Clinical Research

Clinical research is a branch of healthcare science that determines the safety and effectiveness of medications, devices, diagnostic products and treatment regimens intended for human use.

Clinical research includes:

  • Medical and behavioral research involving volunteer participants
  • Investigations that are carefully developed and conducted with clinical outcomes recorded
  • Identification of better ways to prevent, diagnoses, treats, and understands human disease
  • Trials that test new treatments, clinical management and clinical outcomes, and long–term studies
  • Strict scientific guidelines

There are ethical and regulatory constraints for the design and conduct of a clinical trial that have to be considered. Ethical principles are to protect participants before a drug is put forward for a clinical trial.

The United States National Institutes of Health (NIH) has stipulated seven ethical requirements:

  1. Social value
  2. Scientific validity
  3. Fair subject selection
  4. Informed consent
  5. Favorable risk-benefit ratio
  6. Independent review
  7. Respect for human subjects

Clinical Trials

Clinical trials are prospective studies on human subjects that are designed to answer specific questions about drugs, treatments, devices or new ways of using known interventions, generating safety and efficacy data. Clinical Research is a study that tests how well an intervention works in a group of people, Tests for new methods of screening, prevention, diagnosis, or therapy. During a trial, additional information is learned about an intervention, its Risks, and its effectiveness.

Clinical Research Process

  • Pre-clinical testing
  • Investigational New Drug Application (IND)
  • Phase I (assess safety)
  • Phase II (test for effectiveness)
  • Phase III (large-scale testing)
  • Licensing (approval to use)
  • Approval (available for prescription)
  • Post-marketing studies (special studies and long-term effectiveness/use)

Pre-Clinical Testing

Pre-clinical testing is required before testing humans. Pre-clinical testing is often conducted on animals many pre-clinical studies use a review Committee to determine if the use of animals is warranted. The review Committee also checks to see if the research can be improved by reducing or replacing animals. Laboratory and animal studies are conducted to find out if there is a potential benefit of the drug, vaccine, or other product and to explore general safety concerns. If a vaccine, Drug has a potential benefit, it is prepared for human testing. Pre-clinical testing takes approximately three to four years.

Investigational New Drug Application (IND)

For studies that involve a new vaccine, drug, after completing Pre-clinical testing, an investigational new drug application (IND) must be filed describing the results of pre-clinical testing and how future studies will be conducted. The U.S. Food and Drug Administration (FDA) have 30 days to review the IND. If the FDA approves the IND within 30 days, the test drug can precede to a phase I trial.

Phase I (Assess Drug Safety)

The Phase I clinical trial is the first experiment in which a drug is tested on the human body. The primary aim of the trial is to assess the safety of the new drug. Phase I trials are usually conducted with open label, i.e. the subjects are aware of the drugs that they are being given. For the first time, the Test drug is introduced to humans. Testing occurs in a small number of healthy volunteers (20 to 100). This initial phase of testing usually lasts several months to 1 year. The goals of phase I clinical trials are Assess safety for humans as well as select the dose to be used in future studies. During phase I, the study is designed to determine how the human body reacts and what side effects occur as dosage levels is increased.

Open-label Study: A trial in which subjects and investigators know which product each subject is receiving.

Phase II (Test for Safety and Effectiveness)

A phase II study provides comparative information about relative safety and effectiveness and efficacy. Most phase II studies are randomized trials. This means One group receives the experimental Test Drug other Control group receives the current standard treatment or Placebo. Some phase II studies are blinded, This means participants and researchers do not know who receives the experimental test drug, this testing may last from several months to 2 years it may involve from 100-300 participants.

Phase III (Large-Scale Testing)

The objective of Phase III is to confirm the efficacy of the drug in a large patient group. This trial is normally conducted in several hospitals in different demographic locations, to determine the influence of ethnic responses, so this trial is also known as a multicentre trial. This large-scale testing (1,000-3,000 participants/volunteers) provides a better understanding of efficacy. Most phase III studies are randomized and blinded trials with specific entry criteria. Phase III studies typically last several years. After a phase III study is successfully completed, a company can request NDA from the FDA.

Randomization: The Process of assigning trial subjects to treatment or control groups using an element of chance to determine the assignments in order to reduce bias. Blinded study: A study in which the subject, the investigator, or anyone assessing the outcome is unaware of the treatment assignment(s).

Control group: The group of subjects in a controlled study that receives no treatment, a standard treatment or a placebo.

Placebo: A pharmaceutical preparation that does not contain the investigational agent.

Multicenter trial: Clinical trial conducted according to a single protocol but at more than one site and therefore, carried out by more than one investigator.

Food and Drug Administration (FDA): The United States regulatory authority charged with, among other responsibilities, granting IND and NDA approvals.

New Drug Application (NDA): An application to FDA for a license to market a new drug in the United States.

Licensing (Approval to Use)

After all three clinical trial phases are complete and, if the research demonstrates that the test drug is safe and effective, a New Drug Application (NDA)/ Biologics License Application (BLA) is filed with the FDA. This NDA/BLA must contain all scientific information compiled over the course of the trials. The FDA is allowed at least 6 months to review the NDA/BLA. However, this review Process can sometimes take up to 2 years, depending on specific country requirements.

Approval (Available for Prescription)

Health care providers are able to prescribe. Even after approval, reviews continue to ensure safety over time. For example, all cases of adverse events must be reported, and quality control standards must be met (Sometimes studies to evaluate long-term effects are also required). The accelerated approval Process for serious diseases is designed to help development of treatments and to fill an unmet medical need to get important new treatments to patients faster.

Post-Marketing Studies

Post-marketing studies (special studies and long-term effectiveness/use) are also called Phase IV studies. These studies are often performed in special populations not previously studied (for example, children or the elderly) the studies are designed to monitor Long-term effectiveness and/or efficacy and the impact on a person’s quality of life. Some studies help determine the cost -effectiveness of a therapy compared to other traditional and new therapies.

Industry Regulations and Standards for Clinical Trials

Every trial has to be approved and carried out under regulatory compliance to comply with GCP requirements. Different countries have different requirements for clinical trials. Two organizations that carry significant regulatory weight are the combined forces of the US Food and Drug Administration (FDA) and International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). It is the role of public regulatory authorities to ensure that pharmaceutical companies comply with regulations. There is legislation that requires drugs to be developed, tested, trialed and manufactured in accordance to guidelines so that they are safe and patient’s well being is protected. Regulatory authorities perform the watchdog role to ensure that animal studies comply with Good Laboratory Practice (GLP), clinical trials are performed in accordance with Good Clinical Practice (GCP) and drugs are manufactured under current Good Manufacturing Practice (cGMP) conditions.

ICH stands for "International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use". ICH is a joint initiative involving both regulators and research-based industry representatives of the EU, Japan and the US in scientific and technical discussions of the testing Procedures required to assess and ensure the safety, quality and efficacy of medicines. The objective of ICH is to increase international harmonization of technical requirements to ensure that safe, effective and high quality medicines are developed and registered in the most efficient and cost effective manner.

The ICH Topics are divided into four major categories:

  • Quality (Q): Those relating to chemical and pharmaceutical Quality Assurance
  • Safety (S): Those relating to in vitro and in vivo pre clinical studies
  • Efficacy (E): Those relating to clinical studies in human subject
  • Multidisciplinary topics (M): Topics which do not fit uniquely into one of the above categories

Efficacy Topics

  • E3: Structure and Content of Clinical Study Reports
  • E4: Dose-Response Information to Support Drug Registration
  • E6: Good Clinical Practice: Consolidated Guideline
  • E8: General Considerations for Clinical Trials
  • E9: Statistical Principles for Clinical Trials
  • E10: Choice of Control Group and Related Issues in Clinical Trials

ICH's mission is to make recommendations towards achieving greater harmonization in the interpretation and application of technical Guidelines and requirements for pharmaceutical product registration The ICH Steering Committee and its sub-committee are comprised of representatives from six parties that represent the regulatory bodies and research-based industry in the European Union, Japan and the USA Region Regulatory Body Research Based Industry Japan MHLW - Ministry of Health, Labour and Welfare JPMA-Japan Pharmaceutical Manufacturers Association Europe EU - European Union EFPIA - European Federation of Pharmaceutical Industries and Associations USA FDA - Food and Drug Administration PhRMA - Pharmaceutical Research and Manufacturers of America

U.S.FDA: Branch of the United States Department of Health and Human Services and regulates all aspects of pharmaceutical industry. 21 CFR Part 11 Compliance: In your research the computer systems used to collect and analyze data must be validated to meet the FDA requirements for electronic records and signatures.

Title 21 of the Code of Federal Regulations (CFR): Parts applicable to clinical research:

  • Part 11 - Electronic Records and Signatures
  • Part 50 - Protection of Human Subjects
  • Part 54 - Financial Disclosure by Clinical Investigators
  • Part 56 - Institutional Review Boards
  • Part 312 - Investigational New Drug Application
  • Part 314 - Applications for FDA Approval to Market a New Drug or an Antibiotic Drug
  • Part 600 - Biological Products
  • Part 812 - Medical Devices

Departments and Roles in a CRO

Contract Research Organization: CRO is an organization that provides support to the Pharmaceutical, biotechnology, and medical device industries in the form of research services outsourced on a contract basis. A CRO may provide such services as Pre Clinical Research, Clinical Research, Clinical Trials Management, Clinical Data Management, Bio statistics and SAS Programming. A Typical Clinical Research Organization may contain the following departments:

  • Clinical Operations
  • Data Management
  • Medical writing
  • Pharmacovigilance
  • Biostatistics/ SAS Programming
  • Regulatory affairs

Key Functions in Clinical Operations

  • Managing and coordination of study conduct
  • Monitoring and tracking of project milestones to ensure that the project runs within timelines.
  • Participation as appropriate to expedite the feasibility and conduct of global trials
  • Ensuring that the regulatory submission are of acceptable quality
  • Support Investigator as and when required (e.g. Finalization of Investigator agreements and contracts, Finalization of Protocol and CRF)

Key Functions in Data Management

  • Data Entry
  • Database creation, Updating, Validation and Database lock
  • Data Quality Check
  • Data Clarification Form generation
  • Coordination with Operations team to resolve queries

Protocol: Clinical research is conducted according to a plan (a protocol) or action plan. The plan describes what will be done in the study, how it will be conducted, and why each part of the study is necessary. The protocol or plan is carefully designed to safeguard the participant's health and answer specific research questions. Case Report Form (CRF). A printed, optical, or electronic document designed to record all of the protocol-required information to be reported to the sponsor for each trial subject.

Key Functions in Quality Assurance

  • Facilitate audits which are conducted by clients locally within the country
  • Ensure that all staff within the country has a complete and current training record
  • Facilitate the auditing of suppliers and vendors used by company within the country
  • Ensure that all GCP compliance issues with sites or elsewhere are raised to the Director of Quality Assurance and the Director of Medical Affairs
  • Maintaining version control of SOPs to ensure that all staff are following the correct and up to date SOPs

Key Functions in Pharmacovigilance

  • Collect, follow-up, transmit all local adverse events, and pregnancy cases, to Global Pharmacovigilance.
  • Process cases in accordance with Global and Local Pharmacovigilance Procedures.
  • Answer ADR and ADR case processing questions from local Regulatory Authorities and Health Care Professionals.
  • Submit the report able ADRs, to the local Regulatory Authorities according to the national regulations and answer any subsequent questions in collaboration with the Global Pharmacovigilance.

Key Functions in Medical Writing

  • Clinical Study Protocol Writing
  • Documentation for Regulatory Submission
  • Technical Documentation for Clinical Trials
  • Writing Medical Cases
  • Managing SAEs during clinical trials
  • Closely associated with regulatory department in preparing narratives for submission

Standard Operating Procedure (SOP): Detailed, written instructions to achieve uniformity of the performance of a specific function. Adverse Drug Reaction (ADR): Any noxious and unintended response associated with the use of a drug in humans.

Serious Adverse Event (SAE ): Any untoward medical occurrence that at any dose: results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or is a congenital anomaly / birth defect.

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