Clinical Research: An Introduction

Introduction to Clinical Research

• New medicines and treatments must undergo testing to ensure they are safe and effective before being given to people.
• This testing process is known as clinical research.
• Clinical research helps to study how well new medicines, medical devices, or treatments work
• Clinical research also determines if there are any side effects or risks involved and how a disease can be prevented, diagnosed, or its symptoms managed.
• Clinical research is conducted on real people (participants or volunteers).
• Scientists use clinical research to find out whether new treatments can be trusted.

What Are Clinical Trials?

• Clinical trials are part of clinical research involving planned experiments or observations where new treatments or medical approaches are tested on people.
• Clinical trials test new drugs that haven't been approved
• Clinical trials find new uses for already approved drugs
• Clinical trials explore different ways of administering drugs, such as turning an injection into a pill.
• Clinical trials check herbal or alternative treatments like vitamins and develop new ways to diagnose diseases.
• Clinical trials study procedures or medicines to reduce symptoms.
• Clinical trials must be planned to ensure patient safety and accurate results and also need permission from health authorities before starting.

Who Runs Clinical Trials?

• The Principal Investigator (PI), a medical or scientific expert, plans and leads the trial.
• Government agencies must approve the trial
  • FDA in the USA
  • CDSCO in India
• The Institutional Review Board (IRB) ensures the safety and rights of the patients involved
• The Data and Safety Monitoring Board (DSMB) reviews the trial as it happens to ensure everything is going well.

Where Are Clinical Trials Conducted

• Clinical trials occur at one hospital or research center.
• Clinical trials can occur at many centers in different cities or countries, and these centers are often managed by Clinical Research Organizations (CROs).

Who Pays for the Trials?

• Clinical trials can cost billions of dollars, requiring sponsors.
• Sponsors provide money and resources once the trial plan is approved and can be:
  • Government bodies
  • Pharmaceutical companies
  • Medical device companies
  • Non-profit organizations

Types of Clinical Trials

• Treatment Trials: Test new drugs, drug combinations, or surgeries.
• Prevention Trials: Aim to stop diseases from happening or coming back using medicines, vaccines, or lifestyle changes.
• Diagnostic Trials: Develop better tests to find out if someone has a disease.
• Screening Trials: Test methods to detect diseases early.
• Quality of Life Trials: Look for ways to make life better for people with long-term illnesses.

Problems or Risks with Clinical Trials

• Side effects: New treatments can cause unexpected reactions.
• Effectiveness: The new treatment may not work better than existing ones.
• Extra work: Participants may need to fill out more forms and visit the hospital more often.

What Is a Clinical Trial Protocol?

• A clinical trial protocol is a detailed plan or guide that explains how a clinical research study will be carried out that includes:
  • Why it's being done
  • Who can take part
  • How it will be conducted
  • How the results will be analyzed.
• The protocol ensures participants are safe, the study answers important research questions, and the data collected is reliable and accurate.

What Does a Protocol Contain?

• A well-written protocol includes:
  • Background and Purpose of the Study: Explains why the study is being done, what past research says, and what the researchers hope to find out (the objective).
  • Who Can Take Part (Eligibility Criteria): Includes inclusion criteria (who is allowed to join) and exclusion criteria (who is not allowed to join).
  • Study Design and Methods: Details how the study will be carried out, what tests, procedures, and medications will be used, and how long the study will last.
  • End of the Trial Definition: Explains when the trial is officially over (usually after the last visit of the last participant).

Important Details About Protocols

• Controlled and Versioned Document: Every protocol must have a version number and date to avoid confusion.
• Track Changes: Any updates or changes made to the protocol should be recorded to easily see what has changed and why.
• Patient and Public Involvement (PPI): Including input from patients and the general public helps to design better studies to ensure the protocol meets the needs of real people, not just researchers.
• Protocol Registration: Most medical journals and ethics boards require the trial to be registered publicly before the first participant joins the study to ensures transparency and prevents hidden or fake studies.

Why Is a Protocol Important?

• Ensures participant safety by outlining clear steps to protect those taking part in the trial.
• Provides consistency so everyone involved (researchers, doctors, nurses) follows the same plan.
• Helps with ethics approval because the Human Research Ethics Committee (HREC) reviews the protocol and may reject it or ask for changes if it's incomplete or unclear, which can delay the study.
• Makes data trustworthy with a strong protocol and ensures the results are accurate and meaningful.
• Simplifies Publishing with good documentation making it easier to share the results in scientific journals.

Common Problems and How to Avoid Them

• Many trials face issues like unclear instructions, missing information, and confusing goals.
• These issues can be avoided by spending more time on planning, writing a clear and complete protocol, and reviewing the protocol with experts before submission.

Conclusion

• Writing a clinical trial protocol is like building the blueprint for a research project.
• A detailed, clear, and scientifically strong protocol increases the chances of the trial being successful and getting approved quickly, which is beneficial to all parties involved.

Protocol Development

• When developing a clinical trial protocol, the complexity of the document depends on the type of study being conducted.
  • Interventional and multi-site studies need more detailed protocols.
  • Studies with minimal risks and those at a single site require less detail.
• A research protocol is a detailed document that describes:
  • Background: Why the study is being done.
  • Objectives: What the researchers want to learn.
  • Study Design: The methods and steps of the research.
  • Methodology: How the research will be done (procedures, treatments, measurements).
  • Statistical Considerations: How the data will be analyzed.

Sections of a Protocol

• A protocol typically has three main sections:
  • Background
  • Aim
  • Plan of Investigation
• Each section contains different important information:
  • Background: Explains the reason for the study and gives context, analysis of previous studies, rationale, research questions, and objectives.
  • Aim: This is the purpose of the study and what the researchers aim to discover or prove.
  • Plan of Investigation: Includes study population, procedures, variables, and statistical methods; it is the how-to guide of the study

Clinical Trial Protocol Template

• A clinical trial protocol template is a ready-to-use guide to help researchers create their protocol, especially for studies involving human medicines (as per Clinical Trials Regulations 2004).
• The template provides specific details to guide researchers through the process of creating a clinical trial protocol that are useful for both commercial and non-commercial trials
• According to the ICH GCP guidelines, a clinical trial protocol should include these key sections:
  • Basics: Title page
  • Context: Background Information
  • Aims: Objectives/Purpose
  • How the study is structured: Study Design
  • Who can participate: Selection and Exclusion of Subjects
  • Participant treatment: Treatment of Subjects
  • How effectiveness is measured: Assessment of Efficacy
  • Measuring safety of treatment: Assessment of Safety
  • Handling negative reactions: Adverse Events
  • When study can be stopped: Discontinuation of the Study
  • Data analysis: Statistics
  • Maintaining standards: Quality Control and Assurance
  • Ethical considerations: Ethics
  • Data protection: Data Handling and Recordkeeping
  • Sharing results: Publication Policy
  • Timeline: Project Timetable
  • Background sources: References
  • Extra Details: Supplements/Appendices

Template Details

• General Information: Contains basic information about the trial, including protocol title, sponsor and monitor information, authorized signatories, medical expert, investigator information, trial site, and laboratory information.
• Background Information: Gives context and explains the investigational product, nonclinical studies, risk and benefits, route of administration, population to be studied, and compliance statement.
• Clinical Trial Objectives and Purpose: Defines the main goal of the trial, including primary and detailed objectives.

Trial Design

• It ensures the trial is scientifically valid and trustworthy which includes:
  • Trial Endpoints
  • Trial Type/Design
  • Avoiding Bias

Trial Endpoints

• These are the main things the researchers are measuring which includes - Primary endpoint: The most important result. • Secondary endpoints: Additional results.

Trial Type/Design

• Explains how the trial will be conducted. • Examples: Double-blind , placebo-controlled, parallel design which will include a diagram showing the flow of procedures

Avoiding Bias

• This is done
  • Randomization: Assigning participants by chance to different groups.
  • Blinding: Keeping patients and/or researchers unaware of which treatment is given to avoid biased behavior or interpretation.

Treatment Details

• Including the which treatment or drug is used along with the
  • Dose,
  • How often it's given
  • How it's given.

Participation Duration

• This explains how long each participant will be in the study and includes all phases -treatment, observation, and follow-up.

Stopping Rules

• This includes all conditions under which a participant or even the entire study may be stopped which includes an Example: Serious side effects.

Accountability

• This is for tracking of the drugs used, including placebos and comparisons.

Code Maintenance and Breaking

• Codes keep the treatment secret (blinded). • There should be a clear method for breaking the code in case of emergencies.

Data Collection (CRFs)

• CRFS = Case Report Forms. • Specifies what data will be directly recorded and used as primary evidence.

Inclusion Criteria

• Includes Conditions that must be met to join (e.g., age 18–65, diagnosed with diabetes).

Exclusion Criteria

• Conditions that prevent someone from joining (e.g., pregnant, other major illnesses).

Withdrawal

• This includes the
  • Rules for when/how a participant may leave. • What data will still be collected. • Whether participants will be replaced. • Follow-up care for withdrawn participants.

Treatments Administered

• Includes the
  • Names
  • Doeses
  • Schedule
  • Route
  • Schedule
  • Length of treatment

Allowed and Not Allowed Treatments

• includes Some medications are allowed alongside the trial drug (e.g., rescue medication). • Some are not allowed as they might affect the results.

Monitoring Compliance

• Ensuring participants take the medicine as required.

Statistics in Clinical Trials

• Statistical Methods is used to measure • Sample Size • Significance Level • Stopping Criteria • Handling Missing or Bad Data • Deviations from the Plan • Who Will Be Analyzed

Ethics in Clinical Trials

• All trials must follow ethical principles, which include:
  • Confidentiality: Keeping personal data private.
  • Informed Consent: Participants must understand and agree before joining. • Citation and Integrity: Using data and sources honestly.

Quality Control and Quality Assurance

• QC (Quality Control): Ensures participants are safe and the data is accurate during the trial. • QA (Quality Assurance): Ensures the entire trial follows the rules and standards (protocol, GCP, regulations).

Financing and Insurance

• Who is funding the trial. • Insurance coverage for participants (in case of harm). • Any financial benefits or compensation to participants. Conflict of interest disclosures.

Publication Polic

• Explains how the trial results will be shared : In journals, conferences, posters, oral presentations, etc, and ensures transparency and proper acknowledgment of contributors.

Supplements

• They include additional information or attachments that support the main protocol which includes: • These might include extra study forms, detailed data tables, or reports. • Protocols must be approved and signed by the Chief Investigator and others involved. • In multi-site trials, each site's investigator should sign to confirm their agreement to follow the current version of the protocol.

What is an IRB/IEC?

• An Institutional Review Board (IRB) or Independent Ethics Committee (IEC) is a group of people responsible for protecting the rights, safety, and well-being of people who take part in a clinical trial or any research involving humans.
• They review:
• The trial protocol (the plan for the study)
• The investigators (doctors/researchers)
• The facilities (where the study is done)
• This review ensures that the research is ethical and safe for the participants.
• Other names for IRB include:
• Ethics Review Board (ERB)
• Research Ethics Board (REB)

Why is the IRB/IEC Important?

They:

• Protect people who join the research.
• Make sure the research is fair, legal, and ethical.
• Approve the methods used to get participants' consent.
• Check if researchers and their sites are suitable for the study.

Formation of IRB/IEC

• The committee must have a mix of members:
• A minimum of 5 members as per ICH GCP Guidelines
• At least one member with a non-scientific background (e.g., a lawyer, teacher, or social worker).
• At least one member who is not part of the institution or research team (independent member).

Why This Diversity Is Important

• Scientific/medical members understand the technical side.
• Non-scientific members understand how the research may affect people socially or culturally.
• Independent members avoid any conflict of interest and give an outsider's unbiased view.

Key Qualities of IRB/IEC Members

• Should have scientific knowledge and/or ethical awareness.
• Should be independent thinkers.
• Should be fair and unbiased.
• Should represent different backgrounds and genders for a balanced view.

Working Procedures of IRB/IEC (Ethics Committee)

• The main job of an IRB/IEC is to protect people who are participating in clinical trials.
• People are often called “subjects” or “participants”.

What does the IRB/IEC do?

It: – Makes sure the trial is safe and ethical. -Checks if the rights of participants are protected.

• Reviews all documents before the study starts.
• Monitors the study while it is ongoing.
• Ensures that participants are treated well and that their personal information is kept private.
• Checks if payments to subjects are fair.

Documents Reviewed by IRB/IEC

• Research Protocol – the detailed plan of the study.
• Informed Consent Form – what participants sign to agree to join.
• Recruitment Ads – any posters, flyers, or ads to find participants.
• Information given to subjects – anything they will read or see before or during the study.
• Investigator's Brochure – information about the drug or product being studied.
• Details of payments or compensation to participants.
• Investigator's qualifications – their updated CV or proof of training.
• Any other information the IRB/IEC may need to make sure people are safe.

Steps in Getting IRB/IEC Approval – Flowchart

• The investigator submits the research proposal and documents to the IRB/IEC.
• IRB/IEC checks if the information is complete and correct: -If YES, they move forward with the review.
• If NO, they send it back to the investigator to make corrections.
• IRB/IEC reviews the study in a meeting and discusses safety, ethics, and more.
• After the review, three things can happen:
  • Approval/Favorable Opinion: Trial can start. -Modification Required: Investigator must make changes before approval.
• Rejection/Disapproval: If the trial is not ethical or safe, it is rejected.
• Once written approval is received, the study can begin.

Ongoing Responsibilities of IRB/IEC

• Check on the trial regularly (continuing review).
• Ensure any changes to the study are approved before they happen.
• Stop or suspend a study if it's putting people at risk.
• Review and respond to new information, side effects, or serious problems.
• Key Important: No clinical trial can begin until written approval is given by IRB/IEC.

5.4 INFORMED CONSENT PROCESS AND PROCEDURES

• In clinical research, it's very important to protect the rights, safety, and well-being of people who take part in studies using a process called informed consent. Informed consent means that a person agrees to join a research study only after they fullyunderstand:
• What the study is about
• What will happen to them
• What the risks and benefits are
• That joining the study is their choice
• Their decision must be: Fully informed and Voluntary.
• This process is not just a one-time thing it starts before the study and continuesthroughout the study.

Why is Informed Consent Important?

• It respects the participant's right to make their own decisions.
• It protects them from harm.
• It ensures that they are not tricked or forced into joining a study.
• It keeps the study ethical and legal.

Background of Informed Consent

• Came from the Nuremberg Code (1947) after unethical experiments during World War II and strengthened by the Declaration of Helsinki (1978) and Now, it's part of WHO and Good Clinical Practice (GCP) rules.

GCP helps ensure that:

Research is done properly

• Results are reliable
• Participants are respected and protected.

Goals of Informed Consent

• Give clear information about the study.
• Give time to think before deciding.
• Answer all questions the subject has.
• Ensure that the subject understands the study.
• Get the person's voluntary agreement.
• Keep updating them during the study.
• Check again and again if they still agree to continue.

Tools Used in Informed Consent

To help people understand, these tools can be used of : Consent forms, Pamphlets, Internet articles, Instruction sheets and Videos or audio

Investigator's Responsibilities

• The investigator (research doctor or person conducting the trial) must:
• Get consent before starting any study activity and choose a quiet, private place for discussion. Explain the study in simple language and give enough time to think and let them take the form home if needed
• Check reading ability and if someone can't read, an impartial witness should help Answer every question and makesure the person really understands the study Makesure the person is not being pressured and keep checking during the study if the person still agrees
• Share any new important information, especially if risks change, and ask if they stillwant to continue.

Elements of Informed Consent

• There are three important parts of informed consent:Voluntarism, Information Disclosureand Decision-Making Capacity
• a) Voluntarism
  • The person must freely decide without pressure, should not be forced, bribed, or trickedand the way of taking consent must be approved by the IRB/IEC. b) -) Information Disclosure, the subject must be told their health condition and purpose of the study and what will be done (procedures, medicines) Risks and possible side effects and benefits they may or may not get and What happens if they don't join along with Other treatment options and that they can leave the study anytime

Considerations for Informed Consent

• When taking informed consent from someone for a clinical study, there are certainimportant points to keep in mind, like: • Risks need to belower with minimum risk to the participants • Disclosure of payments or benefits
• when participants are getting any money, gifts, or reimbursement, they must be told clearly • Being aware consent may be skipped or "waived"
• For example, in emergency or public health studies, it has to be legal
• It doesn't harm the person's health, finances, or legal rights • Be extra careful due a bias affecting how participants behave

Key Steps for getting informed consent

1. Participant can understand:

• They should sign and date it themselves.

2. Participant Can't Give Consent – LAR Needed

• People with severe mental illness or are Unconscious The participant may need :
• Their Legally Acceptable Representative (LAR), like a parent or guardian, mustgive consent
• The participant should be told as much as they can understand.

3. Participant or LAR Can't Read, they should read:

• Provide a witness - someone who may not be connected with the case can attest, if necessary to provide consent. 4 - Participant Has a Regular Doctor, the primary physician can be contacted

5. Emergency Situations

• If: The participant can't give consent and LAR is not available the , Special steps (mentioned in the protocol) must be followed and IRB approval is what's needed

Summary of Consent Process

Here's a quick step-by-step flow:

1. Identify what kind of participant is involved.
2. Use the right method ( Direct consent, Consent from LAR,)
3. Provide clear and simple information.
4. Make sure the participant understands.
5. Ensure it's voluntary and without pressure.
6. Keep checking and re-confirming throughout the study.
7. For special or emergency cases, follow protocol and legal rules.

Getting Started

• People joining clinical studies has to be given the right information while informing them of a Clinical trial step by step and clear and simple wording to engage in the clinical trial, even if the participant is unwilling

Role of the Subject

• To ask questions throughout the entire case and should not be able to be forced into anything, needs to be provided with an interpreter must the participant requires the need of it.

Final Steps in the process

• Signing and giving final consent but the document is for those whom do not require interpreters, those whom require interpreters must ensure is provided through the help of the medical staff assigned to the operation

Waivers in situation

• The common rule requires it to be a study under low risk , it cant alter a right within the patients life, the study requires the test through ethical standpoints

Emergency or therapeutic situations:

• Quick tests can sometimes be an alternative and the patient has the ability to refuse at anytime which can apply if the patient contains ethical complexities whom requires the need of surrogates to act on their behalf

What is GCP

• GCP means following ethical and research standards using human subjects and in multiple countries but this must always be top priority across all trials
• GCP requires to have these standards and requires to follow these: - Trials must be ethical by the declaration of helsnki requires everyone to act accordingly to the study - You're to proceed knowing the potential of safety and standards along the way

Following GCP

• The research data is trustworthy -New medicines are approved faster
• Reduces cost and risk to the study

People responsible for GCP

-First started by who and had a global standard by ich to create and ethical code research

The 13 requirements

• Ethical requirements
• You're to proceed knowing the potential of safety and standards along the way
• Must provide previous research and or data to support the medicine
• Follow the process and cannot alter or add to the process
• Qualified medical staff

GCP Continued

• Must ensure education is well trained and they must agree with informed consent - Handing data should be accurate • The trial would be easy to verify
• Ensure confidentiality Products must follow GMP guidelines

Quality and Assurance in GCP

• Systems should all be in place to ensure quality of the studies and there must always been
  • Good data and respect towards patients
  • The approval of medicine should be made fast

What is a Principal Investigator

• A Principal Investigator (PI) is the main person in charge of a clinical trial site
• Responsibilities:
  • Making sure the trial is carried out in a manner that is considered respectful and follows the rules that has been outlined

PI Responsibilities According to the FDA

The PI:

• Signs the procedures
• Must understand responsibilities before signing any forms
• Delegates tasks to certified teams.
• Monitors data
  • Must stay in constant communication with the board

Following the study

• Any protocol must match to the documents and must have approval from all boards
• Must review any device the subject may use
• Monitor patients and the study at a regular basis and they are allowed to leave and must have it wrote down.

Randomization and blinding

• Monitor patients and the study at a regular basis and they are allowed to leave and must have it wrote down.

Summary

• PI must always be cautious of their procedures and always plays a lead role that has ethical approval and conducted with certified professionals.

Who is a Sponsor

• A Sponsor is a company, organization, or individual who initiates, manages, and funds a clinical trial.
• They are responsible for the planning, oversight, and quality of the entire trial.
• Have a Data and Safety Monitoring Board (DSMB). The Sponsor must:
  • Maintain a Safety board
  • Maintain the data and privacy of the enrollees

The Sponsor must appoint the right people to:

1. Design the trial plan (protocol)
2. Supervise the entire trial
3. Manage and check the study data
4. Protect participants' rights and safety
5. Track how well the study is being carried out
6. Do the data analysis (statistics)
7. Write up study reports In short: Sponsors run the entire project from start to finish.

Monitors in Clinical trials

• A Monitor is a person who checks how a clinical trial is being run at each site.

What they check?

- If the study is going as planned

• the Rights and safety of others
  • the Team is following the protocol
• Most of the time, they visit the research sites

Role of the Monitors

• Check Data and compare to the medical records
• Supports after any side effects the enrollee may have
• Verifies teams qualifications

What Is Clinical Trial Management?

• It is designed to test new medical treamtments or drugs ensuring and it is important to ensure the run is well for efficiency and effectiveness

The Goal Of trial Manger

• Helps plan the trial's process and helps solves complex issues to give an ethical study, these also give proper budgets

Trial Success

• It's up to the manager to help create a environment that helps patients with efficiency and give proper data to create a fair study

Inefficient systems

Use string digital system to solve all issues and must be clear and to meet all requirements and be flexible

Efficient re-cruitment

The success of trials relays upon these tactics and it's their goal to hit the needed requirements of those enrolled and or selected

Following Training GuideLines

• there is no standard training or requirements and they all learn on the job so there needs to be a universal test for efficiency.

Summary of the Trial

Must maintain a great ethical standpoint and communicate professionally and this will lead to clear success that values progress under medical standards

What is Clinical Trial Monitoring

• It is to ensure the clinical trial is being carried out for several main goals. That.
  • Participants are safe and the data being recorded is clear and there are no federal reg violations.
  • A Sponsor must appoint someone that has experience to run the trial It's important for a better result.

Several Trial Methods

• Traditional monitors who must physically check all data to confirm the process
• Non traditional must collect the data as the trial goes on

Reviewers for the board

• Sponsor personnel (Data managers, research assistants) • IRB (Ethics Committee) • DSMB and CEC (Clinical Endpoints Committee)

Ways to Monitor

• In person is highly recommended but not possible for all
• Review for unusual or missing data
• 100% of the earlier data is expected to be check

risk-adapted monitoring

• Depending on several factor more safety is needed
• • Type, design, and complexity All will save time and meet quality in the process

Trial Oversight Committees (TOC)

• TSC they are the make or break for continuing and DMC for the data.

• Monitoring is a team efforts but it to give quality is followed ethically

Pharmacovigilance?

• Pharmacovigilance means monitoring the safety of medicines to identify, assess, and prevent adverse effects. During clinical trials, to make sure the drug is safe for human use.

Trials

• Are done to safely test the medicines and requires:
  • Ich- GCP for all practice
• Cioms- ethical standards Declaration of helsinki for principles

Stakeholders include

Sponsors: Designs the trial protocol and Informed Consent Form (ICF) and Sets up systems like the data to collect and must Report serious adverse events (SAEs) quickly to stakeholders.

Ethical protocols of clinical trials

• Follow the protocols under ibs to show concerns • Can reject or suggest changes which make the enrollee take part at whatever time and should be tested by expert teams.

Communicating saftey should be

• between several parties such as investigators or regulatory bodies and must report procedures