Module 8
Conducting Clinical Trials
VASCPROG 603
Research Ethics and Biostatistics
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Introduction
Clinical trials are a special type of research study. Because they test drugs and medical devices that will be used on human subjects, they are subject to governmental regulation and they have to conform to strict rules.
This module has been included because it is likely that students will be involved in human clinical trials in the course of their future careers, and it is not a subject that is normally taught at the graduate level.
The module doesn’t cover the design of clinical trials. This is a very complicated subject and if you are ever in the position in which you plan to design a clinical trial, you will need professional help (I’m not talking about therapy, although by the time you are done you might need it!). You will definitely need the services of a professional team that will include a statistician and an MD to advise on patient care.
What is covered are the issues you should be aware of when considering running a clinical trial, or what to expect if you become an investigator on an industry-sponsored clinical trial.
The module addresses practical issues such as:
The responsibilities of the Principal Investigator
The infrastructure needed to carry out clinical trials, including staff and space How to decide if an industry-sponsored clinical trial is worth doing
How to evaluate an industrial contract and budget and when to ask for more How to avoid being sued!
Drug Trials - Phases
Before a drug is ever tested on human subjects, it must be tested in at least two non-human species, usually rodents and dogs. These are called pre-clinical trials (clinical trials are those done on humans).
Once a drug passes the animal testing stage, the sponsor applies to the regulatory board for IND (investigational new drug) status. In the US, if the FDA doesn't disapprove the Investigational New Drug (IND) application within 30 days, clinical trials may begin.
In Canada, this is part of the mandate of Health Canada. Information on this process can be found at the following link at the:
Therapeutic Products Directorate
The animal studies are extensive and must include toxicity data on short and long term dosing. The results of all the animal testing are presented in the Investigator’s Brochure. Although the results of these studies can predict likely toxicities in humans, this is not foolproof, but usually it is enough to prevent fatalities at least.
After the animal studies have been concluded satisfactorily there are four clinical trial phases for human research.
The whole idea of these phases is to limit any dangers by testing for safety and effectiveness with the smallest possible population.
After each stage the sponsor has to report all results to the appropriate Federal agency (FDA/Health Canada) and get their permission to carry on to the next phase. All the stages have strict guidelines regarding objectives, design, data analysis etc. The phases are described on the following page.
Continued Phase I Phase II Phase III Phase IV 2
Drug Trials – Phases
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Phase III - Efficacy. Phase III trials involve testing the new drug against a placebo, or against the best currently available treatment, using randomized groups. These trials usually involve several thousand human subjects to confirm earlier findings of effectiveness. Phase III trials often take several years to complete, and only 25-30% of all IND’s complete this phase successfully. If they are satisfactory, the sponsor files a New Drug Application. Review and approval takes 2 to 3 years from the conclusion of clinical trials.
While the application for a new drug is pending, post-marketing studies may be carried out (Phase IV) to gather further safety data. Phase IV trials are sometimes required by the regulatory bodies, but they are more often employed by the pharmaceutical companies, because they enable the drug to be used by more patients before it comes to market. If the results are good, this can create further demand for the drug during a time which otherwise would be downtime.
Phase I - Toxicity and Dosage. Phase 1 trials are to establish a safe dose range in humans, who are usually healthy volunteers, rather than the intended patient population. Information is gathered on how the drug is absorbed and distributed within tissue, how it is excreted and how long a dose acts on the body. These trials are usually completed within a year and involve under a hundred research subjects. Approximately 70% of all IND’s (Investigational New Drugs) are successful in this phase of trials. This stage is to establish dose schedules and to ascertain any preliminary side effects. Phase II - Safety and Efficacy. These trials are designed to precisely assess the drug's effectiveness and to detect major adverse reactions (side effects). These trials range from 100 to 1,000 subjects and last 2-3 years. Approximately 33% of all IND’s are
Types of Clinical Trials
In the broadest sense, clinical trials can be classified as academic or industry-sponsored.Clinical Trials are a systematized form of research study that evaluates some type of treatment, medical technique or device, to see if it performs better than a current treatment, or than nothing at all. This can include anything that must be tested on human subjects. Examples might be new drugs, radiation techniques, vaccines, gene therapy, a different surgical technique, or an improved biopsy machine. Clinical trials are heavily regulated and monitored by Federal agencies and they are expected to conform to Good Clinical Practice (GCP) guidelines, which were covered in Module 2. All pharmaceutical companies must conduct extensive clinical trials on their new drugs by law, and must carefully monitor all their approved, currently marketed drugs.
Some medical researchers decide to devise their own clinical trials. Examples would be that a researcher may want to test a new application of an already approved drug, but perhaps for a different disease, or they may want to look at the effects that certain vitamins may have on a particular disease or condition. This would be classified as an academic clinical trial, as opposed to an industry-sponsored trial, where a pharmaceutical company conducts clinical trials to develop a product for profit.
Academic clinical trials are subject to the same Federal regulations as industry-sponsored trials and must be approved and monitored by a University Research Ethics Board.
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Types of Clinical Trials
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Federal granting agencies will award funds for clinical trials, making it similar to other research where the investigator must justify the methodology and design to secure peer-reviewed funding, and also receive ethics approval for the project.
The NIH and NCI in the US have a useful website that describes many aspects of academic clinical trials for researchers and for patients at:
Cancer Clinical Trials
Although this web site is focused on cancer, it offers excellent information that is relevant to all clinical trials.
Post-Marketing Trials
Post-marketing trials, sometimes called Phase 4 studies, may have different objectives. These studies are often performed in different patient populations than the original trial (such as children or the elderly). Another reason is to monitor a drug's long-term effectiveness and impact on a patient's quality of life, sometimes these studies are designed to determine the cost-effectiveness of a drug therapy relative to other traditional and new therapies.
Trials for Medical Devices
Clinical trials that involve medical devices rather than drugs follow the same rules as drug trials. There is a description of the processes involved at the following link, which is aimed at medical device companies:
Canadian Regulatory Processes for Medical Devices
Clinical Equipoise
An important concept in human clinical trials is clinical equipoise, sometimes referred to as the principle of equipoise, and it is about the ethics of assigning patients to different treatment arms of a trial.
If, in the middle of an ongoing trial, a clinician comes to believe that one treatment arm is better than another, then a clinical dilemma arises – isn’t the clinician ethically obligated to give that drug/treatment, or to assign patients to the arm of the trial he/she feels will most benefit the patient? Of course, this would negate the clinical trial by sending randomization out of the window.
The concept of clinical equipoise was developed to allow clinical investigators to continue a clinical trial without violating ethical principles. Clinical equipoise means that there is genuine uncertainty
within the expert medical community
about which treatment is better.
So even if the clinical researcher is sure that an experimental treatment is better, clinical equipoise allows the trial to be finished ethically until the final statistical results are published. At that point the results should convince the expert medical community and clinical equipoise will no longer be met – there is no longer any uncertainty about the value of the treatment.
Industry-sponsored Trials
If you ever become an investigator on an industry-sponsored clinical trial, then all the work of planning the design, methodology, analysis, and how to measure the pharmacokinetic data is carried out by the sponsor company. All the investigator has to do is closely follow the methodology laid down in the clinical protocol.However, agreeing to be an investigator on such trials is a serious undertaking. The investigator must sign a contract agreeing to adhere strictly to the protocol. By signing, the investigator is assuming the legal responsibility that the trial will be carried out according to the contractual agreement.
An investigator who violates the protocol is liable to be prosecuted by federal agencies. There have been some fairly high profile criminal trials in the news in the last decade, some of them in Canada. The most common reason for the prosecution was because the investigator deliberately included patients who did not fit the inclusion/exclusion criteria. This was done in the belief that being in the clinical trial would benefit the patient, by having them treated by a drug that would be otherwise unavailable to them. Unfortunately, even such high-minded motives are not excused by the courts. Health Canada has a guide on record-keeping for clinical trials, which is updated regularly. This is essential reading if you are involved in a clinical trial.
Industry-sponsored Trials
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Once the protocol is in place, the individual investigator cannot change any aspect of the protocol. If there is a belief that something in the protocol is harming subjects, the investigator should inform the sponsor company and the local REB. At that point, the investigator must wait for instructions from the sponsor. The local REB may terminate the trial at the local site if they decide there is a legitimate danger, but they must give a detailed, written account to the sponsor why this decision was made. The sponsor must inform the Federal regulatory agency, who may decide to terminate the entire trial, or the sponsor company themselves may decide to terminate.
For industry trials, each investigator must get the sponsor’s permission before they give talks on the research, or publish anything to do with the study. The sponsor will want to see anything of this nature and they have the option to refuse permission.
One of the main advantages of conducting industry-sponsored clinical trials is that they can generate a significant amount of research income that can be used by the investigator for their own research. Some of these funds may be a portion of the local institutional overhead that is given back to the investigator, and the rest will be the funds that remain after all the payments for clinical trial procedures have been made.
Before you sign the contract, try to ensure that the clinical trial budget will cover all costs and generate enough extra income to make the trial a worthwhile enterprise. If not, then you might rethink your reasons for taking on the responsibility and the work involved.
Why are Clinical Trials so Important?
Clinical trials are very costly to carry out interms of time, money, and risk. It takes about 12 years to bring a drug to market at a cost of about $800 to $900 million US. Only 1 in 5000 drugs ever makes it to market, but a blockbuster drug such as the statin drug, Lipitor, makes in excess of $5 billion per year.
In addition to the expense, clinical trials require a huge team effort, are very labour-intensive, and require a great deal of advance planning.
However, clinical trials are considered the gold standard for testing treatments safely. They are the only credible way to scientifically test a product or procedure.
Most of the disadvantages of planning and funding the clinical trial is borne by the sponsor.
The sponsor assumes the financial and legal risks associated with developing the drug.
Clinical trials can generate research funds that the PI can use for their own research.
Clinical trials can enhance the PI’s academic and clinical reputation.
Why would a researcher consider being a PI on an industry-sponsored trial?
Things to Consider for Clinical Trials
There are several aspects to considerbefore embarking on clinical trials: – Legal Aspects – Patients – Support Staff – Time – Space LEGAL ASPECTS
This is not just a matter between the Investigator and the Sponsor. Because clinical trials are regulated at the federal level, it is a serious offence to violate the trial protocol in any way that will affect the results of the trial. The most common violations are to knowingly include patients who don’t fit the criteria, to enroll family members, or to make up data for patients who don’t exist. This can involve a jail sentence, fines, and will certainly involve being blacklisted from any future clinical trials.
PATIENTS
Patients enrolled in clinical trials need to be treated somewhat differently from regular patients. Eligible patients are like gold. Patients who enroll in clinical trials do so for a variety of reasons, one of which may be a sense of altruism. Many clinical trials involve tedious or unpleasant procedures and may not directly benefit the participant.
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Things to Consider for Clinical Trials
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PATIENTS continued
If any of these patients voluntarily drop out of the study, perhaps because they have been kept waiting for too long due to disorganization on the Investigator’s part, this represents a significant loss to the sponsor. Although some of the patient’s data may be usable, it is far more valuable if the patient completes the study.
It is important that research patients be treated with extra consideration and be kept waiting as little as possible. Sometimes the patient may participate because they enjoy the extra attention and the feeling they are being useful. Recognizing their efforts, either by more personal attention from the trial staff, or by a thank you card may be all that is required to encourage a patient to stay in the trial.
Low patient recruitment is a major problem for all clinical trials and there have been many studies that look at the barriers to patient accrual. Although most patients like the idea of clinical trials, common reasons for declining include:
The length of individual visits and total duration of the trial
The risk of being assigned either to the placebo arm or to a treatment arm that has unacceptable conditions
Worries about taking unapproved medication or radiation from imaging studies.
It is important to try to anticipate such worries and discuss them before the trial, which may help improve recruitment and lead to less dropout during the trial.
Things to Consider for Clinical Trials
continued
CLINICAL TRIAL SUPPORT STAFF
Running clinical trials will often involve hiring extra staff. As the Principal Investigator is not usually involved in all stages of the clinical trial, it is critical to have staff who are experienced in setting up and running trials. The most important position is the Clinical Trial Coordinator, who may or may not need to be a registered nurse.
If the trial will involve drawing blood or other medical procedures, then a qualified person will be required to carry these out, although this need not necessarily be the clinical trial coordinator.
It is not a good idea to train someone on the job, unless they will be supervised by an experienced clinical trial coordinator. Completing Case Report Forms requires specialized knowledge. Even if a prospective person has nursing training, this is not a substitute for clinical trial experience. Carrying out research trials is different from seeing patients in clinical practice.
The ideal candidate will understand research methods and have experience in working on clinical trial case reports.
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Things to Consider for Clinical Trials
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Finding experienced staff to work on clinical trials may be a challenge. There are training courses in the U.S. that will also certify people as Clinical Research Associates (CRAs), but candidates must already be working in clinical trials. These courses are designed to supplement training rather than training personnel from scratch.
There are other staff you need to consider besides a coordinator. Diagnostic tests are likely to be needed and technicians may have to be certified by a standardized centre before they can work on the trial. These staff also need to be motivated and to understand that they may have to work more flexible hours.
Sometimes clinical staff may feel resentful of the extra demands on their time. They need to be rewarded for their efforts and to feel they are part of the team. It helps to include them in the start-up meeting so they get a chance to meet others and to develop a sense of personal involvement in the trial.
Things to Consider for Clinical Trials
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TIME
Clinical Trials can take up a lot of time. Not only that, but the time sequence of the clinical events in the protocol may be very demanding. For example, patients may need to undergo certain tests 24 hours after a procedure, or a drug trial may involve pharmacokinetic tests. These are usually performed in Phase I trials, but may be included in Phase II trials.
Pharmacokinetic studies measure how drugs are absorbed, metabolized, and then eliminated from the body. This involves blood and/or urine tests to be taken at very specific times around the clock. The patients need to understand the time constraints before they enter the study and the clinical trial staff must be available at the required times.
SPACE
Another major consideration in running clinical trials is the question of space. If extra staff have been hired to help run the trial they will need space for a desk to fill out the paperwork generated by clinical trials, and they will need secure storage for all the subject files and for the study drug.
Other things to consider are:
Where will subjects be examined and tested? Will a hospital bed be required? Where will subjects wait to be examined? How many visits are involved in the trial? How often are these visits?
Will you need space for storage of clinical trial equipment?
If there are MDs involved in the trials, how will study patients be fitted into their clinical practice?
How to Decide if a Trial is Worth Doing
First, read the Clinical Trial Protocol andthe Investigator’s Brochure.
The first thing to consider is the drug or device:
– Is it potentially worthwhile?
– Do you think it would it benefit the recipients?
– Does it have an IND number? As you know from Module 3, if the product doesn’t have a Canadian IND number, then it cannot receive ethics approval.
The Clinical Trial Protocol
The quality of the protocol is usually a good indication of the overall quality of the trial. Clinical trials are very expensive and most companies will not jeopardize the considerable outlay by having a sloppy protocol, but it does happen, particularly with small trials.
The protocol should contain all the information you would need to complete a Research Ethics Board submission. (Module 3).
It should include:
– The objectives of the study
– A description of how the sample size was calculated
– A description of the proposed statistical analysis
– A detailed description of risks and how to report adverse events
How to Decide if a Trial is Worth Doing
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The Clinical Trial Design (part of the
Protocol)
Think about the design and methodology of the trial. Does it seem sound from a clinical perspective?
What is expected of patients enrolled in the study? Are the demands reasonable? If you were a patient, would you consider participating?
Will the design and the inclusion/exclusion criteria make recruitment very difficult? Recruitment will usually be the biggest headache – you can’t have a successful trial without subjects.
The Investigator’s Brochure
This is a thorough description of the drug itself, including:
– All the details of the development and testing to date, including toxicity data.
– A description and quantification of any adverse events and side effects experienced at any phase of the trials.
If the drug in question has reached Phase III trials this means that the FDA/Health Canada has approved the process so far, but the side effects also should be taken into consideration when evaluating the trial.
How to Decide if a Trial is Worth Doing
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Laboratory Procedures
Check the laboratory procedures listed in the protocol:
Will they involve using a nurse coordinator? (this will add to your budget).
Can the procedures be contracted out? Are the facilities available to carry them out? Often, a centralized lab is part of the clinical trial. Samples must be prepared and packaged and shipped by overnight courier to the central lab. For blood samples this often involves the use of a local centrifuge and storage of dry ice, which will be used for packaging the samples. Dry ice must be stored in a –80 degrees freezer.
Are payments for all the laboratory procedures included in the budget? Sometimes tests need to be repeated. There is usually no provision for this in the budget, but this eventuality should be discussed with the sponsor.
The budget is another crucial area in deciding to be involved in a clinical trial. It is explained on the following page.
The Budget
The budget must cover all research costs. Usually the budget will itemize all individual tests and procedures and give an amount for each. If a physical examination of patients is required, this must be performed by an MD.
Make sure the budget includes payment for any extra staff. This can be negotiated before the contract is signed.
There should also be an itemized amount for subject remuneration. This is covered in more detail later in the module, but subjects should not be out of pocket by participating in the trial. Some patients may have to travel long distances and will need extra remuneration. This should be negotiated before the budget is signed off.
The budget also must include payment of any hospital or university overhead charges, depending on where the trial is conducted. The sponsor should be informed of the Research Ethics Board submission costs, but these should not be listed in the formal budget – the REB will invoice the sponsor company separately. Some tests may need to be repeated – there should be provision for this in the budget.
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The Budget
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Extra expenses incurred by clinical trials that are not usually included in the budget:
Recruitment - advertising costs Paper and office supplies
Locking filing cabinets for secure storage of data
Pager rental and telephone costs. The clinical trial coordinator may need a pager so that patients have a contact number for emergencies.
Courier costs. Most documents will need to be sent by courier rather than regular mail. The sponsor should provide their account number with a courier company that shipments can be charged to.
Never accept any trial that pays for each “completed” patient. Lots of patients may start the study, but may then drop out for any one of many reasons. You will still have to remunerate each patient for any trial visits and you will not receive any compensation for the work that has been carried out.
Third-Party Trials
There is a difference between a clinical trial offered directly from a pharmaceutical company, and one which comes through a third party, which is usually a Contract Research Organization (CRO).
A CRO is a for profit company that specializes in all aspects of designing and running clinical trials, and which contracts out their expertise to pharmaceutical companies.
Smaller pharma companies without the in-house expertise to organize a clinical trial can pay a CRO to carry out the trial.
Even the large pharmaceutical companies will often use CROs to help monitor their trial. These organizations do not produce the drug or device, but their role can cover anything the pharmaceutical company cannot do in-house, such as the research design and methodology, or they may just be hired to provide Clinical Research Associates (CRAs). The CRA is the company representative assigned to particular sites to monitor the clinical trials. They make sure that the facilities are adequate and will usually hold an initiation visit with the staff at the site to perform a dry run of the trial procedures. These companies perform a valuable service and are generally very helpful to individual investigators.
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Third-Party Trials
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However, sometimes CROs can have a less benign aspect. Instead of working together with the pharmaceutical company and the investigator, they approach the pharmaceutical company and negotiate a total package to carry out the entire trial. The CRO then farms out the clinical trial to individual investigators, who have no direct contact with the pharmaceutical company who are producing the drug.
These trials are often offered with an inflexible budget that may not even cover the costs of the trial. The CRO pockets any excess funds - the proceeds that otherwise would go to the individual investigators. Since these research proceeds are one of the major reasons why anyone would consider taking on a trial, you should be very careful about accepting a trial from a third party agency. From the investigator’s point of view such an arrangement also can be inefficient. The amount of work may be increased, as there may be separate reporting to both the CRO and the pharmaceutical company.
The Sponsor and the Contract
When the sponsor first contacts apotential investigator, they ask them to sign a confidentiality agreement before the investigator is allowed to see the clinical trial protocol. Under the terms of the confidentiality agreement the investigator may not discuss details of the trial with anyone not bound by the same agreement.
The sponsor will usually organize a start-up meeting in some central location to explain the clinical trial and the drug or device in detail. This gives the investigators chance to meet each other and ask questions about the trial.
Signing the contract means the investigator agrees to carry out the clinical trial strictly according to the protocol, and also that the budget is acceptable.
Because clinical trials are federally regulated, it becomes a criminal offense to violate the contract.
The contract will also need to be approved and signed by the investigator’s institution. If the clinical trials involve patients and require hospital staff and procedures, these must be evaluated by the hospital before the contract is signed.
The CRA (Clinical Research Associate)
The CRA (Clinical Research Associate)is an employee of the drug company who is assigned to monitor the different sites involved in clinical trials. Depending on the number of sites, there may be several CRAs.
CRA is a professional certification recognized internationally, which gives people with a background in health care or science, training in all aspects of clinical trials. This includes government legislation, clinical trial development, and monitoring obligations.
The CRA is responsible for making sure the paperwork is complete and the trial is being conducted correctly.
The CRA is the point person between the investigator and the sponsor, and they are usually the first person to call with any concerns or questions about the trial. Serious adverse events should be reported to the CRA as soon as possible. In the case of medical emergencies the confidential subject code must be broken to find out to which treatment arm the patient was assigned. Instructions on how to do this will have been given to the Principal Investigator at the start of the trial. If this becomes necessary the CRA should be contacted as soon as possible to inform them of the details.
Another duty of the CRA is to be present at any audits of the trial and to carry out the close out of the trial.
Research Ethics Board (REB)
The role of the Research Ethics Boardwas covered in detail in Module 3. This is just a reminder of the most important points regarding clinical trials.
Once an investigator has agreed to be part of a clinical trial and has signed a contract, they must apply for, and be granted ethics approval before any patients may be enrolled in the trial. The pharmaceutical company will not proceed until they have a copy of the ethics approval.
Drugs tested in Canada must be approved by the Health Products and Food Branch of Health Canada and have been issued an IND (investigational new drug) number. All drug trials must go through an IRB/REB, usually at each site a trial takes place.
The ethics approval must be kept updated with any changes and at least a yearly review (called Continuing Ethics Review). This review involves completing a form stating how many patients have been enrolled, completed, dropped out etc. and a summary of progress, changes to the risk/benefit ratio and the like.
Responsibilities of the REB
To safeguard the rights, safety and well-being of all human research participants. To make sure the budget covers all the research costs. The REB will not approve a submission that makes a charge on the public health system.
To ensure that the research will be carried out by qualified individuals.
To ensure that the research design is sound and that the sample size is adequate.
The Clinical Research Impact Committee (CRIC)
Here in London, Ontario, there is anothercommittee who need to be informed in addition to the REB, if the research involves patients in the hospital system, or any type of hospital tests or procedures. This is the Clinical Research Impact Committee (CRIC) at London Health Research Institute (LHRI). Other institutions will have similar regulations. This committee oversees clinical trials and other research that require hospital services, such as any type of imaging, laboratory tests, or the use of their personnel. This is to make sure that the hospital system is not overburdened by the demands of research, and to make sure that the costs of these services are covered by the clinical trial/research budget.
None of the costs of clinical trial or research-related procedures may fall on the public health care system.
The CRIC Office also needs to negotiate the contract with any industrial sponsors to make sure the overhead is included in the budget.
In the case of pharmaceutical company sponsored clinical trials, the Research Office of LHRI levies a 30% overhead charge on the total clinical trial budget to the company. This levy must be included in the clinical trial budget. This is a normal procedure for all industry-sponsored clinical trials in all countries. A percentage of this overhead may be funneled back to the Principal Investigator of the local site, which can be used for other research related activities.
There are separate CRIC forms to be submitted with the Ethics Submission form. The CRIC form requires a copy of the project budget and a list of all the hospital procedures involved in the research.
Recruitment and Subject Payments
Recruitment of subjects is likely to be themost difficult problem in running a successful trial. Investigators usually overestimate the number of subjects who will be eligible, and how many eligible subjects will agree to participate. It can be very frustrating to find subjects who match all the criteria but who are not interested in the study.
The Research Ethics Board has guidelines on the recruitment of subjects. One of these concerns any advertising that the study will require. The REB will need to approve the advertisements as part of the original ethics approval process. This is to make sure the ads do not make unreasonable claims about the treatment in question, or violate the civil code of Canada, which states that people may not be paid to participate in research.
If any logos of participating universities, hospitals, or other institutions are used, they will need to approve the ads as well.
Subject Payments
The issue of subject payments must be handled with care as, by law, people are not allowed to be paid to participate in research. This is to protect people who need money so badly that they will agree to be in research studies that they would otherwise refuse.
Research studies are only allowed to compensate people for their travel expenses, meals, parking etc.
The wording used in any written material, such as advertisements and Letters of Information for Subjects should refer to compensation for expenses and time, rather than payment for services.
Informed Consent
The subject of informed consent is very important and was covered in more detail in Module 3, but the main points will be reiterated here.
The Letter of Information for Subjects and the Informed Consent document are part of the ethics approval application. The REB must approve both before issuing the ethics certificate.
There are very strict rules regarding informed consent. It is illegal to enroll a subject in a clinical trial (or any research) before the full nature of the research has been explained to them, and they have agreed to participate by signing the informed consent document.
When the clinical trial is audited, failure to obtain or to produce any enrolled patient’s signed consent form would be reason to disqualify a site from the clinical trial.
There are special rules for obtaining informed consent from any subject who is part of a vulnerable population, such as children, illiterate or handicapped persons etc. These are described at:
Requirement for Free and Informed
Consent
Informed Consent
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When the investigator or the clinical trial coordinator explains the trial to a potential subject, it is not a good idea to minimize or ignore unpleasant aspects of the trial just to boost enrollment.
Care should be taken in how the new therapy or device is explained to patients. They should not be led to expect that the treatment will benefit them. The patient may be randomized to the placebo arm of the study, or the drug may not, in fact, be effective. After all, that is why the clinical trial is being conducted in the first place – to see if it is effective or not. Patients who experience no real benefit may be more inclined to drop out of the trial before the end, particularly if their expectations were high.
The person explaining the trial should be very honest about what the research participant can expect. It should be explained to them that they are helping to gather information that will allow progress to be made, and even if the drug doesn’t help them, the information may help others in the future.
Also bear in mind that some patients may want to please you by agreeing to be in the study when they don’t really want to. Such patients may drop out early, or be non-compliant with the demands of the trial.
Confidentiality and Data Handling
Sponsors
Sponsors have a heavy investment in investigational new drugs and they need to control information on the clinical trial while still observing FDA requirements. Investigators must sign a confidentiality agreement before they are allowed to see the protocol. They must not talk about the clinical trial with anyone not bound by the same confidentiality agreement.
The clinical trial contract also has clauses that prohibit investigators from revealing information from the trial, including any research papers, without the sponsor’s written permission.
Subjects
The reality is that patient confidentiality is somewhat limited. The Letter of Information usually states that information will be revealed to federal agencies, research ethics boards, and any other applicable agencies.
There is a legal requirement that only the study codes that are assigned to subjects are to be used on all documents and specimens for the clinical trial, and never the subjects’ names. There must be locked storage of subject data throughout the trial.
Most clinical trial records must be maintained in secure storage for at least 25 years after the trial is completed. If space is unavailable at the investigator’s site, there are medical records companies, which will store the records in coded boxes, so they are retrievable if the need arises. This is in case of lawsuits arising from unforeseen long-term effects of an experimental drug or treatment.
Patient Records – The Case Report Form
During the clinical trial the coordinator isresponsible for keeping the records for each subject in a binder; one binder per subject. The binder contains all records pertaining to that patient and the Case Report Forms (CRF’s). Each case report form is required by the federal regulatory agency and they follow a fairly standardized format that must be approved by that agency.
Completing the Case Report Forms is very time consuming. A black pen must be used to complete them. Every single question must be answered and every box either contain an answer or be marked n/a.
One of the main duties of the study monitor is to make sure the CRFs are complete. If questions or procedures have been missed then often the subject must be asked to return for a further visit.
One of the major purposes of the CRFs is to be able to recreate the exact sequence of events during the course of the clinical trial for each subject. This will be necessary if anything happens to a patient, or if a patient sues the sponsor for damages.
There are different CRFs for the subject’s medical history, any medications they are taking, and many others, including the adverse event forms.
Drug Storage and Accountability
The supplies of the investigational drugmust be kept under secure storage. Some drugs must be kept in refrigerated conditions, which also must be in a secure area.
Hospital pharmacies may agree to store and dispense the drug for a fee. They will also keep the drug records for the study.
There must be strict accountability of the drug on the premises, and all drug given out to patients. This entails keeping a count of each individual pill or dose.
Some drugs must undergo preparation before being administered e.g. drugs in powdered form must be mixed with saline before being injected. These steps must be recorded on the appropriate forms.
It is especially important that drugs that are part of blinded procedures are carefully dispensed and recorded.
Any unused drug must be returned to the pharmaceutical company for disposal. No study drug must ever be given out by anyone, except as prescribed to patients in the clinical trial. These are not sample drugs.
Equipment
The sponsor usually provides any equipment required to carry out specialized tests during the trial, such as ECG machines, etc. They will also train the clinical trial staff in the use of the equipment and how to transfer data to the correct source. ECG data is usually transmitted over a telephone line directly to the reading centre employed by the sponsor.
Usually the equipment is provided short-term for the duration of the trial and then must be returned.
Adverse Events
There are different classifications of adverse events for drug trials:
Adverse Event (AE)
Serious Adverse Event (SAE) - also includes Serious Adverse Drug Reaction (Serious ADR)
Unexpected Serious Adverse Event
An adverse event is any illness, symptom, abnormal laboratory finding, or other condition that arises while a patient is taking a study drug or treatment. Whether or not an adverse event (AE) is related to the drug, they must be reported on the Case Report Form. This will include things like a cold, headache, skin rashes, diarrhoea etc.
For any condition that concerns the investigator or the patient, but does not seem to be urgent, it is recommended to first call the CRA of the study and ask advice. For routine illnesses the patient should be encouraged to contact their family doctor who may then decide to refer to another specialist. Any such visits and their outcomes should be reported on the Case Report Form.
Adverse Events
continued
Serious Adverse Events include those which:
Are fatal or life threatening; Result in significant or persistent disability;
Require or prolong hospitalization; Result in a congenital anomaly/birth defect;
Represent other significant hazards or potentially serious harm to research subjects or others, in the opinion of the investigators.
(Taken from the “Policy for Reporting Clinical Study Serious Adverse Events”; National Heart, Lung, and Blood Institute; National Institutes of Health Effective Date: May 1, 2002).
The first priority when a serious adverse event (SAE) occurs is to treat the patient appropriately. The CRA of the pharmaceutical company should be notified as soon as possible and the requisite forms must be submitted.
The Research Ethics Board of your institution will also need to be notified and should have their own forms that must be completed.
During the study, the pharmaceutical company is required by the FDA/Health Canada to send details of adverse events that have occurred at any of the sites. These are to be sent to the local Research Ethics Board.
Audits and the Audit Trail
There are two types of audit:Internal - Carried out by monitors from the drug company (not the CRA, but auditors trained by the drug company to circumvent any problems that might be revealed by the federal auditors).
Federal Audit - Carried out by FDA/Health Canada Auditors
The audit trail is the documentation that allows reconstruction of events on individual patients. This is why the paper work for a clinical trial is so onerous and detailed – it contains many cross-checks.
The internal audit is a check not just of the PI and the site, but also of the CRA and the company.
By using an internal audit, the drug company wants to ensure that potential problems are recognized before a real audit uncovers them, as this could be pretty disastrous for them, and possibly result in them losing their IND status. This type of audit is just as strict as the real thing.
What both types of audit are looking for are accurate record keeping that shows the trial has been conducted according to the protocol, and that will allow a clear audit trail if anything happens to a patient. Records should be such that the entire course of events for each patient can be tracked. For instance, if a patient needed a coronary bypass while in a clinical trial for a statin drug, the reasons for the coronary bypass should be clearly shown on the source documents (in this case the patients medical file).
Audits and the Audit Trail
continued
An audit can be called up to 2 years after the trial has finished so it is important to make sure that all the documentation is filed properly. An audit can take from a few days to a couple of weeks depending on the size of the study.
The audit is supposed to be random, but may often triggered by certain events, such as data that looks too clean, or by sites that have unusually high enrollment.
Audits are also conducted to look for fraud, or failure to get informed consent.
Premature Termination of the Trial
The trial may be terminated at any time by the sponsor, the regulatory board, or the REB.
Patients must be informed and arrangements made for alternative therapy.
Close Out of the Trial
Once the data has been gathered on the last patient, or the trial has been closed for whatever reason, the CRA will perform the final closeout procedures.
All unused drug must be returned and final records must be kept by the PI for 25 years. After 25 years the data must all be destroyed, including all computer files, according to the guidelines laid down by the REB or other institution rules.
