SAS Clinical Programming: In 18 Easy steps

Owens

STEP 1

INTRODUCTION TO

CLINCAL 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 as well as 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.

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

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

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

Process Flow in a Typical Clinical Trial

Process Flow in a Typical Clinical Trial:

Every clinical investigation begins with the development of a clinical protocol. The protocol is a document that describes how a clinical trial will be conducted and ensures the safety of the trial subjects and integrity of the data collected.

After preparing the protocol we go with CRF designing, The Case Report Form is a data-reporting document used in a clinical study. CRF Collects relevant data in a specific format in accordance with the protocol and compliance with regulatory requirements which Allows efficient and complete data Processing, analysis and reporting and Facilitates the exchange of data across projects and organizations through standardization. CRF designer should always remember that Protocol determines what data should be collected on the CRF. All data must be collected on the CRF if specified in the protocol and Data that will not be analyzed should not appear on the CRF. CRF needs to be finalized and available before an investigator starts enrolling patients into a study. After designing and reviewing the CRF, it is a good idea to send them to sites that will be conducting the study and ask the site personnel for feedback.

Data collection is done using the CRF that may exist in the form of a paper or an electronic version. The traditional method is to employ paper CRFs to collect the data responses, which are translated to the database by means of data entry. These paper CRFs are filled up by the investigator according to the completion guidelines. In e-CRF method, chances of errors are less, and the resolution of discrepancies happens faster. The entries made in the CRF will be monitored for completeness and filled up CRFs are retrieved and handed over to the CDM team. CRF pages are entered by data entry operators. Best practice is, first pass data entry to be completed followed by a second pass or verification step by an independent operator.

Data validation is the Process of testing the validity of data in accordance with the protocol specifications. Edit check programs are written to identify the discrepancies in the entered data, which are embedded in the database, to ensure data validity. Discrepancy is defined as a data point that fails to pass a validation check. Discrepancy may be due to inconsistent data, missing data, range checks, and deviations from the protocol. If the data entered does not pass validation rules then a data query may be issued to the investigative site where the clinical trial is conducted to request clarification of the entry (Data Clarification Form). Any discrepancies between the first and second pass may be resolved such that the data entered is a true reflection of that recorded on the CRF. Where the operator is unable to read the entry the clinical data manager should be notified so that the entry may be clarified with the person who completed the CRF. After a proper quality check and assurance, the final data validation is run. If there are no discrepancies, the SAS datasets are finalized in consultation with the statistician. All data management activities should have been completed prior to database lock. To ensure this, a pre-lock checklist is used and completion of all activities is confirmed. Once the approval for locking is obtained, the database is locked and clean data is extracted for statistical analysis. This data is often referred as raw data by SAS Programmers since this data is not ready for analysis. There may be many things to perform to convert the raw data to analysis ready data which is often refereed as ADS or VAD. Subsequent to ADS creation we go with TLF/ Report generation followed by CDISC conversion and Submission.

STEP 2

INTRODUCTION TO SAS

SAS is a fourth-generation programming language. SAS is a comprehensive statistical software system which integrates utilities for Storing, Modifying, and Analyzing, Graphing data. SAS is used in a wide range of industries such as Insurance, Education, Banking and Life sciences, etc.

Since SAS is a programming language, let us start by looking at a simple SAS program, such as this one:

SAS program is a series of instructions written in the SAS language that are executed in an order. We must adhere to a certain set of rules known as SYNTAX, in order for SAS to be able to read and run your programs properly.

Basic SAS Program Requirements:

♦ SAS statements typically begin with a SAS keyword and must end with a semicolon (;).

♦ SAS statements are not case sensitive, that is, they can be entered in any case.

♦ The words in SAS statements are separated by blanks or special character.

♦ Comments may be used to annotate your program. Two methods are:

A delimited comment begins with a forward slash-asterisk (/*) and ends with an asterisk-forward slash (*/). All text within the delimiters is ignored by SAS.

An alternative comment begins with an asterisk (*) and ends with a semicolon (;).

All text between the asterisk (*) and the semicolon (;) is ignored by SAS.

SAS Program may contain one or more DATA or PROC steps or combination of both.

DATA steps are used to read data into a SAS data set, to modify data values, to check for and correct data errors, and to subset or merge data sets. PROC steps are used to calculate descriptive statistics, to generate summary reports, and to create summary graphs and charts.

SAS Datasets: In order to be able to analyze our data, we need to read it into a file that our SAS software understands. A SAS data set is a file containing two parts: a Descriptor portion and a Data portion.

The data portion of a SAS data set is a collection of data values that are arranged in a rectangular table, such as this:

SAS data set is comprised of variables and observations. The Variables (or columns) are collections of data values that describe a particular characteristic of the thing being measured. Our data set here contains just three variables – the Country, Site, and PI_Name. The Observations (or rows) are collections of data values that typically relate to one particular object.

Rules for User-Supplied SAS Names:

1. The first character must be a letter or underscore. Subsequent characters can be letters, numeric digits or underscores.

2. You can use upper or lowercase letters. SAS Processes names as uppercase regardless of how you type them.

3. Blanks cannot appear in SAS names.

4. When you create SAS data sets, do not use _NULL_, _DATA_, _LAST_.

5. Special characters, except for the underscore, are not allowed

6. All user supplied SAS names should be within the specified length.

SAS Variables:

There are two different types of Variables

1) Character: contain any value: letters, numbers, special characters, and blanks. Character values are stored with a length of 1 to 32,767 bytes. One byte equals one character.

2) Numeric: Stored as floating point numbers in 8 bytes of storage by default. Eight bytes of floating point storage provide space for 16 or 17 significant digits. You are not restricted to 8 digits.

The type of variable is just one of six variable attributes that SAS stores in the Descriptor portion of every SAS data set.

The six attributes that SAS stores are:

1) Variable Name

2) Variable Type

3) Variable Length

4) Variable Format

5) Variable Informat

6) Variable Label

SAS WINDOWS:

SAS is designed to be easy to use. It provides windows for accomplishing all the basic SAS tasks we need to do.

When we first open SAS (Windows O/S), by default, the five main SAS windows open:

♦ Program Editor or Editor Window,

♦ Log window

♦ Output window,

♦ Explorer window,

♦ Results window.

Editor window/ Program Editor: We can use either of these windows to enter, edit and submit SAS programs. The Program Editor window is available on all SAS platforms the (Enhanced) Editor Window, which is available only in the Windows operating environment.

For Windows operating systems, the default editor is called the Enhanced Editor, because it gives you a nudge – through the use of differently colored text.

Log window: The Log window displays messages about our SAS session and any SAS programs that we submit.

SAS uses the following color-coded system to assist you in reading the log:

Notes that SAS wants to report to you are printed in Blue

Warnings that SAS wants to draw to your attention are printed in Green

Errors that cause SAS to abort running your program are printed in Red

(Info), DATA and PROC steps that appear in your program are printed in Black

By default SAS Shows Errors, Warnings, Notes if your submitted program contains them, but Info would not be shown by default (By default Msglevel=N).

Output window: The Output window displays the output from SAS programs that we submit. It automatically opens or moves to the front of our display when we create output.

Explorer window: In the Explorer window, we can view and manage our SAS files and create shortcuts