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Introduction to Clinical Research

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Amy Nguyen

on 26 August 2014

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Transcript of Introduction to Clinical Research

Introduction to Clinical Research

What is a Clinical Trial?
A clinical trial is a series of tests that scientists need to conduct when they come up with new ideas for new drugs, new medical procedures, or medical devices. For the duration of the entire clinical trial process, these are called Investigational Products. When it comes to surgical procedures, often times the new surgical tools/devices have to be FDA approved. FDA approval is needed by drug companies who would like to make claims on their products.
Study Startup
Clinical Trial Audits
Running a Study
For example...
What happens when a scientist at a drug company is looking to come out with a new drug for asthma? He is in a lab with a team of colleagues, and they are looking at the biological mechanisms of asthma. They brainstorm different treatment solutions for asthma by using computer models and other analytical tools to understand what molecules or systems contribute to asthma symptoms. They create a molecule that addresses their solution, and synthesize it in a laboratory.
With a molecule designed, they move onto pre-clinical trials, which involve testing the drug on animals, such as lab rats/guinea pigs. Animal studies are done in the pre-clinical phase to test the effects of the synthesized drug in non-human subjects. With good results from pre-clinical studies, we move onto Phase I Clinical Trials.

The International Review Board (IRB)
Regulatory Documents
Recruiting Study Participants
The PI in your study will refer his/her own patients from their own private medical practice.
PI’s may have a colleague or associate that will refer their patients to your study as well.
Please note that under any circumstance, every prospective participant must be pre qualified by the research clinic in order to assure that they are appropriate trial candidates.

Site Selection Visit
Before your research clinic is awarded the study, a monitor from the sponsor or the CRO will make a physical appearance at the clinical site to make sure that your facility has the resources it needs to accommodate the study in question.
Monitor will ensure that
all PI’s, sub-I’s, and Study Coordinators have received current GCP training
that your facility has a pool of prospective patients,
the lab facility is in order
the CRF and source documentation templates are in place for data collection.

If the monitor confirms that your facility is appropriate for the study, the monitor will send a report to the sponsor and schedule a Site Initiation Visit.
Based on Jim Harvey's speech structures
Between each Phase, the drug companies will update the FDA on its findings, and work with the FDA to come up with the best way to further test the drug safety and efficacy in the upcoming phases.
The first introduction of the drug to healthy human volunteers
Purpose: determine the toxicity level of drug in human body
Once toxicity level is determined, drug company sets its effective dosage level
Volunteers are "in-patients"
Can last from 2-6 weeks
Pays participants an average of $50-$100 a day
The first time the drug is being tested on individuals with the actual medical condition drug is targeting
Purpose: determine safety and efficacy of IP on target disease population
Data from both endpoint objectives are collected and analyzed as well as the pharmacokinetic effects of the investigational product
The last clinical trial that the drug company conducts before submitting an NDA (New Drug Application) to the Food and Drug Administration (FDA)
Will only be initiated once it is established in Phase 2 studies that the drug is reasonably effective and is safe and well tolerated
Purpose: to test and observe the drug on a much longer time scale, and over a much larger patient population
Can last from 8 months - 4 years
Can enroll up to 2500 patients worldwide
Upon completion of the Phase 3 study, the drug company submits an NDA to the FDA, and the FDA responds in one of the three possible ways:
(1) they approve the drug,
(2) they reject the drug, or
(3) the tell the drug company to re-do the Phase 3 study, often by changing a few testing parameters to make the Phase 3 trials more reliable and informative
Purpose: additional testing should the pharmaceutical company decide to market the drug as a treatment to a slightly different condition than was previously planned or to gain more information on the warnings, or side-effects of the drug
Occurs after drug approval and may last between 1 and 8 years.
Gives Pharmaceutical companies the chance to really test the drug for the long term side-effects, in order to better understand how it reacts, and better market the drug to its consumers.

IRB’s govern every single clinical trial
Purpose: To ensure that every patient/volunteer is safe during a clinical trial
Must approve a study before it even begins.
Are in charge of reviewing the study protocols
Must confirm that only patients who are able to make sound judgments on their own health are enrolled in the study
Ensures that control group used in studies are of the best possible FDA-approved treatment when the patient may already be taking drugs for a life-threatening condition
Are independent of the drug companies, and the researchers involved
The Food and Drug Administration (FDA)
Clinical Research Associates (CRA) or Monitors
Types of FDA Audits/Findings
Investigator Meeting
Source Documents
Study Protocol
Reporting Adverse Events
Study Visits
Subject Compensation
Storing the IP
Electronic Data Collection
Study Closeout
Sponsor and CRA audits often will try to help you resolve any issues that they find.
They have a vested interest in your facilities following GCP, in order to make sure that their trials are conducted in the best possible way.
It is important for CROs and sponsor to establish the validity of your facility, if they would like to employ your services in future studies.

FDA staff members meet with researchers, and perform inspections of clinical trial study sites to protect the rights of participants and to verify the quality and integrity of the data.
The FDA has access to all source documentation and CRF’s; however, they do not have access to any financial data regarding your site.
In scheduling an audit, an FDA inspector will call the site and schedule a time, usually within 2 weeks. As soon as the site becomes aware of an audit, all pertinent individuals should prepare themselves. This involves getting all paperwork in order

An adverse event (AE) is any unwanted side-effect, reported by the patient or medical professional, during the study.
This may include headaches, nausea, constipation, and even mental symptoms such as vertigo or depression.
Even a medical event which occurs during the course of the trial, which is not directly tied to the study itself, must still be reported as an adverse event.
The AE document form is reported to the IRB as well as the study Sponsor, and contains the option to specify whether the event was directly related to the present study, or not.
SAE’s are AE’s that typically result in the study participant requiring hospitalization.
A big part of running a clinical trial facility is following, the Clinical Trial Protocols as closely as possible.
Any deviation from the pre-ordained protocols is carefully examined, as it is required that deviations be reported to the IRB
Of course, a PD form must still be filed with the IRB, even if protocol was broken for the safety of the study participants.
Protocol deviations might be minor or major; they might affect the safety of the trial participant or not.
try to be proactive and obtain a protocol waiver from the study Sponsor if you anticipate that a protocol deviation will occur.

This form is filled out by the Study Coordinator, and signed by the study PI before being submitted to the IRB, Sponsor and ultimately the FDA. It contains information on the PI’s name, address, curriculum vitae, and information on all sub-investigators. In essence, this form is a promise, by the clinical trial site to the FDA and the IRB, that the study will be carried out in accordance with GCP.
These forms spell out the recipe to be followed for a particular study, as outlined by the Sponsor, and acknowledged or approved the PI and the IRB respectively. Protocol Deviations, which may occur during the course of the study, are also filed as separate documents in the Regulatory Binder.
Any time the Sponsor decides to re-write, change, add to or remove from, anything from the original protocol to better suit the investigation, these must be approved by the IRB. These approved changes are then stamped, dated, and filed in the Regulatory Folder.
The up-to-date medical licenses of the PI’s and sub-I’s must be kept current by the PI’s, and it ensures that they are still legally permitted to practice medicine during the study.
Also known as the Investigator’s Brochure, it can be up to 300 pages. It contains all the information on the drug being studied in terms of its known effects in animal models, mechanisms of action, quality of treatment, etc.
Advertisement Approval and Letters
: Any advertisement that will be used for recruitment purposes needs to be approved by the IRB and filed in the Regulatory Binder.

The IRB Approval Form
: proving that the study was in fact approved to begin by the IRB.

Lab Certificates
: a copy of lab certificates for all labs that will be processing lab samples for the clinical trial site.

The PI’s and sub-I’s must disclose with the FDA, Sponsor and IRB that there are no conflicting financial interests with the outcome of the study. This is done to add a layer of transparency to study process, and ensure that all matters are being followed in the most ethical way possible. Generally, if any researcher has more than $50,000 in the study Sponsor’s company stock, this needs to be disclosed.
Every item of communication between the IRB, Sponsor, CRO and clinical site must be documented in chronological order. This includes a Final Closeout Form, which is filed once the study is concluded. This also includes all correspondence with your CRA or monitor.
This lists every individual who is involved in the study, from a clerical point of view. Every individual who is assisting the clinical trial process, from the PI to assistants and Study Coordinators, must have their contact information listed, as well as their responsibilities in the trial. This information is important in keeping due diligence on every aspect of the clinical trial process, and making sure that each member is held accountable for following the guidelines of the GCP. It also ensures that individuals are only conducting procedures that they are qualified and delegated to conduct.
Patient and study notes are taken in real-time. Periodically, the study data must be uploaded to a data-bank called the CRF.
This central CRF contains all the information from various sources in reference to the trial, and will be reviewed by a Study Monitor when necessary.
Every piece of source documentation must be uploaded to the CRF in a reasonable time frame, usually 24 hours from the time that information was written, so that the CRF reflects a current overview of the study at any one time.
The CRF’s can be paper based, but are increasingly becoming electronic. These electronic CRF’s are appropriately called eCRF’s or EDC for electronic data capture.
The study drug must be kept on-site, in a double-locked setting.
Only PIs, pharmacists, and Study Coordinators are granted access to the drugs
Study drugs must also be temperature-controlled, and temperature readings should be recorded daily. The products often have temperature restrictions, and it is important to document the compliance of the temperature with the optimal temperature of the room where the study drug is kept.
A good practice for temperature recording is to document both the highest temperature and the lowest temperature of a particular day, in order to make sure it falls within the acceptable range for that particular drug.
Should you notice a temperature excursion, you should quarantine the affected products from the rest of the product lot, notify the sponsor of the temperature excursion, and make plans to send the affected products back to the sponsor.

The PI sits down with the prospective patient and goes over the Informed Consent.
The PI then conducts several basic medical tests to gauge the general health of the patient, including a blood draw and electrocardiogram.
They will confirm any exclusionary treatments that the patient is currently taking
The prospective patient must meet the conditions spelled out in the “inclusion criteria” for the particular study.
If the does not have any exclusionary criteria, then the Randomization visit is established, usually 1-2 weeks from the screening visit.
The patient is randomly assigned one of three classes of drugs, via an automated system which generates random associations:
(1) the actual investigational drug,
(2) a comparative, alternative standard of treatment
(3) the placebo
The patient must keep that same class during all visits and administrations of the drug.
Throughout the study the study participant may be required to come to the clinic for regularly scheduled visits.
At these visits, adverse events are analyzed as well as compliance with the investigational product.
Patient is usually dispensed a new supply of the study drug while the previous supply is returned
Regular study visits are outlined in the study protocol.
Once the study participant has completed the study, or if they choose to withdraw prior to the study completion, a Termination Visit is scheduled.
At this visit the investigational product is returned and any remaining adverse events need to be recorded.
A final blood draw and ECG reading are usually obtained.

Some tips for good budget negotiations include:
Try to negotiate monthly payments. Running clinical research is expensive, and if you are getting paid by the Sponsor on a quarterly basis, you will be using a lot of your own cash between payments.
You should also look in your contract to see if the Sponsor will cover “screen failures.” Screen failures are those patients who do not pass the initial screening process, and therefore cannot be included in the investigation. Try to predict the screen failure rate before-hand, and then gauge whether your contract may cover you for those failures before accepting the study.
It is also important to negotiate a good indemnification clause. This is basically a statement saying that you, as a clinical trial facility, are not held accountable for any harm done to study participants during the course of the study, as long as your facility does follow GCP’s and the study protocol.

In many clinical trials, the study participants receive compensation.
For out-patient studies, patients usually receive $50 for each visit.
During in-patient studies, such as Phase I, patients get paid thousands of dollars as they are giving more of their time to the study.
Investigator meetings are when the sponsor and CRO host large meetings for all the research clinics that will be participating in a particular study.
They will talk about the study, train you on the protocol for a particular study,inform you on what to look out for in terms of adverse events or possible side effects, and get you up to speed for running the trial at your facility.
The investigator meetings are good opportunities for sponsors to voice their concerns regarding the investigation, and share data from previous trials.
They offer opportunities to market with fellow researchers and learn more about your study.
When a study closes out, the research clinic is responsible for keeping the information about the trial on file for between 5 to 10 years, but sometimes up to 20 years.
Often, you store all the records, including the source documents and Contracts, in a separate facility indefinitely.
Each sponsor requires different protocol for how long your facility should store previous trial data.

When the patient is brought into the clinical trial facility, the PI or sub-I will meet privately with the prospective participant and inform the patient of every aspect of the study.
The Informed Consent is an ongoing process as new forms are generated. Whenever there is a protocol amendment, and study participants should be reeducated on every aspect of the study on an ongoing basis.
There should be regular follow-ups to make sure that the patient is still content with the current status of their trial.
Regular Study Visits
Early Termination Visit
A “for cause” audit is triggered if your site raises suspicion that it is not conducting studies as according to GCP. Such an audit reflects poorly on your facility.
A Surveillance Audit is triggered if the data generated from your site differs slightly from the data collected at every other site during a study.
Possible Findings
FDA may find absolutely no deviations

"Minor Deviations"
These deviations will have to be remedied by the clinical facility for future studies, but it does not require any follow up with the FDA.
“Notice of Adverse Findings.”
Filed when serious GCP offenses are found at the clinical trial. It requires that the PI makes a written response to this audit, and it may lead to the data collected from that site to be disregarded in the running trial.

1572 Form
Protocol Documents
Medical Licenses
Drug Brochure
Study-related Correspondence
Financial Disclosure Forms
Protocol Amendments
Delegation of Duties Log
Other Forms
Flyers, physician letters, radio ads, television ads, and digital ads.
Social media , like Facebook and Google, is a promising avenue for attracting new patients.
Ads must be approved by the IRB, ; you must follow GCP’s when creating digital ads.
This is to ensure the safety of the public, by preventing the opportunity for therapeutic misconception or coercion.
Direct Contact
Two Ways to Recruit
Source documentation is any written or spoken information regarding the investigation, which is documented and relevant to the outcome of the study.
Source information can take several forms:
Medical history, disability exam results, current medication, a note that the informed consent has been signed, telephone logs, the patient’s history with prior clinical trials, and medical visits, as documented by the PI.
Coordinator should include information about their experiences with the patient.
What Are Source Docs?
Source Documentation templates are usually created by the individual clinical trial facility, and will vary from facility to facility.
The purpose of this is so that the Source Documentation is highly personalized to the study, itself, rather than a basic, repeated template that shows no variability from trial to trial.
a good tip for creating your source docs would be ask the study sponsor for screen-shots of the Electronic Data Capture (EDC).

How Are Source Docs Made?
The ICF is a form that informs the patient of the purpose of the trial as possible risks and benefits of their participation
The Informed Consent must be approved, stamped, and dated by the IRB before it is given to prospective study participants
Only approved Consents may be used, and these must be documented in the Regulatory Binder
Informed Consent
The Form
The Process
Full transcript