A fundamental distinction in evidence-based medicine is between observational studies and randomized controlled trials. Types of observational studies in epidemiology, such as the cohort study and the case-control study, provide less compelling evidence than the randomized controlled trial. In observational studies,
the investigators only observe associations (correlations) between the
treatments experienced by participants and their health status or
diseases. However, under certain conditions, causal effects can be
inferred from these studies.
Under the right conditions, a randomized controlled trial can provide compelling evidence that the study treatment causes an effect on human health.
Currently, some Phase 2 and most Phase 3 drug trials are designed as randomized, double-blind, and placebo-controlled.
A growing trend in the pharmacology field involves the use of third-party contractors to obtain the required comparator compounds. Such third parties provide expertise in the logistics of obtaining, storing, and shipping the comparators. As an advantage to the manufacturer of the comparator compounds, a well-established comparator sourcing agency can alleviate the problem of parallel importing (importing a patented compound for sale in a country outside the patenting agency's sphere of influence).[citation needed]
The protocol describes the scientific rationale, objective(s), design, methodology, statistical considerations, and organization of the planned trial. Details of the trial are also provided in other documents referenced in the protocol, such as an investigator's brochure.
The protocol contains a precise study plan for executing the clinical trial, not only to assure safety and health of the trial subjects, but also to provide an exact template for trial conduct by investigators at multiple locations (in a "multicenter" trial) to perform the study in exactly the same way. This harmonization allows data to be combined collectively as though all investigators (referred to as "sites") were working closely together. The protocol also gives the study administrators (often a contract research organization), as well as the site team of physicians, nurses and clinic administrators, a common reference document for site responsibilities during the trial.
The format and content of clinical trial protocols sponsored by pharmaceutical, biotechnology or medical device companies in the United States, European Union, or Japan have been standardized to follow Good Clinical Practice guidance[15] issued by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).[16] Regulatory authorities in Canada and Australia also follow ICH guidelines. Some journals, e.g. Trials, encourage trialists to publish their protocols in the journal.
Informed consent is a legally defined process of a person being told about key facts involved in a clinical trial before deciding whether or not to participate. To fully describe participation to a candidate subject, the doctors and nurses involved in the trial explain the details of the study using terms the person will understand. Foreign language translation is provided if the participant's native language is not the same as the study protocol.
The research team provides an informed consent document that includes trial details, such as its purpose, duration, required procedures, risks, potential benefits and key contacts. The participant then decides whether or not to sign the document in agreement. Informed consent is not an immutable contract, as the participant can withdraw at any time without penalty.
However, in designing a clinical trial, this consideration must be balanced with the fact that more patients make for a more expensive trial. The power of a trial is not a single, unique value; it estimates the ability of a trial to detect a difference of a particular size (or larger) between the treated (tested drug/device) and control (placebo or standard treatment) groups. By example, a trial of a lipid-lowering drug versus placebo with 100 patients in each group might have a power of 0.90 to detect a difference between patients receiving study drug and patients receiving placebo of 10 mg/dL or more, but only have a power of 0.70 to detect a difference of 5 mg/dL.
Assigning a person to a placebo group can pose an ethical problem if it violates his or her right to receive the best available treatment. The Declaration of Helsinki provides guidelines on this issue.
In Phase 0 trials are the first-in-human trials. Single subtherapeutic doses of the study drug are given to a small number of subjects (10 to 15) to gather preliminary data on the agent's pharmacodynamics (what the drug does to the body) and pharmacokinetics (what the body does to the drugs).[18]
In Phase 1 trials, researchers test an experimental drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
In Phase 2 trials, the experimental treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.
In Phase 3 trials, the treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow it to be used safely.
In Phase 4 trials, postmarketing studies delineate additional information, including the treatment's risks, benefits, and optimal use.
Before pharmaceutical companies start clinical trials on a drug, they conduct extensive preclinical studies.
Some reasons a clinical trial might last several years:
For clinical trials involving a seasonal indication (such as airborne allergies, seasonal affective disorder, influenza, and others), the study can only be done during a limited part of the year (such as spring for pollen allergies), when the drug can be tested. This can be an additional complication on the length of the study, yet proper planning and the use of trial sites in the Southern, as well as the Northern Hemisphere allows for year-round trials, which can reduce the length of the studies.[21][22]
Clinical trials that do not involve a new drug usually have a much shorter duration. (Exceptions are epidemiological studies, such as the Nurses' Health Study.
At a participating site, one or more research assistants (often nurses) do most of the work in conducting the clinical trial. The research assistant's job can include some or all of the following: providing the local institutional review board (IRB) with the documentation necessary to obtain its permission to conduct the study, assisting with study start-up, identifying eligible patients, obtaining consent from them or their families, administering study treatment(s), collecting and statistically analyzing data, maintaining and updating data files during followup, and communicating with the IRB, as well as the sponsor and CRO.
To be ethical, researchers must obtain the full and informed consent of participating human subjects. (One of the IRB's main functions is to ensure potential patients are adequately informed about the clinical trial.) If the patient is unable to consent for him/herself, researchers can seek consent from the patient's legally authorized representative. In California, the state has prioritized the individuals who can serve as the legally authorized representative.[23]
In some US locations, the local IRB must certify researchers and their staff before they can conduct clinical trials. They must understand the federal patient privacy (HIPAA) law and good clinical practice. The International Conference of Harmonisation Guidelines for Good Clinical Practice is a set of standards used internationally for the conduct of clinical trials. The guidelines aim to ensure the "rights, safety and well being of trial subjects are protected".
The notion of informed consent of participating human subjects exists in many countries all over the world, but its precise definition may still vary.
Informed consent is clearly a 'necessary' condition for ethical conduct but does not 'ensure' ethical conduct. The final objective is to serve the community of patients or future patients in a best-possible and most responsible way. However, it may be hard to turn this objective into a well-defined, quantified, objective function. In some cases this can be done, however, for instance, for questions of when to stop sequential treatments (see Odds algorithm), and then quantified methods may play an important role.
Additional ethical concerns are present when conducting clinical trials on children (pediatrics).
In response to specific cases in which unfavorable data from pharmaceutical company-sponsored research was not published, the Pharmaceutical Research and Manufacturers of America have published new guidelines urging companies to report all findings and limit the financial involvement in drug companies of researchers.[25] US congress signed into law a bill which requires phase II and phase III clinical trials to be registered by the sponsor on the clinical trials website run by the NIH.[26]
Drug researchers not directly employed by pharmaceutical companies often look to companies for grants, and companies often look to researchers for studies that will make their products look favorable. Sponsored researchers are rewarded by drug companies, for example with support for their conference/symposium costs. Lecture scripts and even journal articles presented by academic researchers may actually be 'ghost-written' by pharmaceutical companies.[27] Some researchers who have tried to reveal ethical issues with clinical trials or who tried to publish papers that show harmful effects of new drugs or cheaper alternatives have been threatened by drug companies with lawsuits.[28][29]
For safety reasons, many clinical trials of drugs are designed to exclude women of childbearing age, pregnant women, and/or women who become pregnant during the study. In some cases, the male partners of these women are also excluded or required to take birth control measures.
The sponsor and the local site investigators are jointly responsible for writing a site-specific informed consent that accurately informs the potential subjects of the true risks and potential benefits of participating in the study, while at the same time presenting the material as briefly as possible and in ordinary language. FDA regulations and ICH guidelines both require "the information that is given to the subject or the representative shall be in language understandable to the subject or the representative." If the participant's native language is not English, the sponsor must translate the informed consent into the language of the participant.[30]
The local investigators are responsible for conducting the study according to the study protocol, and supervising the study staff throughout the duration of the study. The local investigator or his/her study staff are also responsible for ensuring the potential subjects in the study understand the risks and potential benefits of participating in the study; in other words, they (or their legally authorized representatives) must give truly informed consent. They are responsible for reviewing all adverse event reports sent by the sponsor. (These adverse event reports contain the opinion of both the investigator at the site where the adverse event occurred, and the sponsor, regarding the relationship of the adverse event to the study treatments). They also are responsible for making an independent judgment of these reports, and promptly informing the local IRB of all serious and study treatment-related adverse events.
When a local investigator is the sponsor, there may not be formal adverse event reports, but study staff at all locations are responsible for informing the coordinating investigator of anything unexpected. The local investigator is responsible for being truthful to the local IRB in all communications relating to the study.
The IRB scrutinizes the study for both medical safety and protection of the patients involved in the study, before it allows the researcher to begin the study. It may require changes in study procedures or in the explanations given to the patient. A required yearly "continuing review" report from the investigator updates the IRB on the progress of the study and any new safety information related to the study.
In the US, the FDA can audit the files of local site investigators after they have finished participating in a study, to see if they were correctly following study procedures. This audit may be random, or for cause (because the investigator is suspected of fraudulent data). Avoiding an audit is an incentive for investigators to follow study procedures.
Alternatively, many American pharmaceutical companies have moved their clinical trials overseas. By doing this they are able to avoid many of the FDA’s regulations, since the FDA rarely investigates clinical trials outside the United States. This increases the ability of pharmaceutical companies to skew results obtained overseas in order to make a profit. [32]
Different countries have different regulatory requirements and enforcement abilities. An estimated 40% of all clinical trials now take place in Asia, Eastern Europe, and Central and South America. "There is no compulsory registration system for clinical trials in these countries and many do not follow European directives in their operations", says Dr. Jacob Sijtsma of the Netherlands-based WEMOS, an advocacy health organisation tracking clinical trials in developing countries.[33]
Beginning in the 1980s, harmonization of clinical trial protocols was shown as feasible across countries of the European Union. At the same time, coordination between Europe, Japan and the United States led to a joint regulatory-industry initiative on international harmonization named after 1990 as the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)[34] Currently, most clinical trial programs follow ICH guidelines, aimed at "ensuring that good quality, safe and effective medicines are developed and registered in the most efficient and cost-effective manner. These activities are pursued in the interest of the consumer and public health, to prevent unnecessary duplication of clinical trials in humans and to minimize the use of animal testing without compromising the regulatory obligations of safety and effectiveness."[35]
Under the right conditions, a randomized controlled trial can provide compelling evidence that the study treatment causes an effect on human health.
Currently, some Phase 2 and most Phase 3 drug trials are designed as randomized, double-blind, and placebo-controlled.
- Randomized: Each study subject is randomly assigned to receive either the study treatment or a placebo.
- Blind: The subjects involved in the study do not know which study treatment they receive. If the study is double-blind, the researchers also do not know which treatment is being given to any given subject. This 'blinding' is to prevent biases, since if a physician knew which patient was getting the study treatment and which patient was getting the placebo, he/she might be tempted to give the (presumably helpful) study drug to a patient who could more easily benefit from it. In addition, a physician might give extra care to only the patients who receive the placebos to compensate for their ineffectiveness. A form of double-blind study called a "double-dummy" design allows additional insurance against bias or placebo effect. In this kind of study, all patients are given both placebo and active doses in alternating periods of time during the study.
- Placebo-controlled: The use of a placebo (fake treatment) allows the researchers to isolate the effect of the study treatment from the placebo effect.
Active comparator studies
Of note, during the last 10 years or so, it has become a common practice to conduct "active comparator" studies (also known as "active control" trials). In other words, when a treatment is clearly better than doing nothing for the subject (i.e. giving them the placebo), the alternate treatment would be a standard-of-care therapy. The study would compare the 'test' treatment to standard-of-care therapy.A growing trend in the pharmacology field involves the use of third-party contractors to obtain the required comparator compounds. Such third parties provide expertise in the logistics of obtaining, storing, and shipping the comparators. As an advantage to the manufacturer of the comparator compounds, a well-established comparator sourcing agency can alleviate the problem of parallel importing (importing a patented compound for sale in a country outside the patenting agency's sphere of influence).[citation needed]
Clinical trial protocol
Main article: Clinical trial protocol
A clinical trial protocol
is a document used to gain confirmation of the trial design by a panel
of experts and adherence by all study investigators, even if conducted
in various countries.The protocol describes the scientific rationale, objective(s), design, methodology, statistical considerations, and organization of the planned trial. Details of the trial are also provided in other documents referenced in the protocol, such as an investigator's brochure.
The protocol contains a precise study plan for executing the clinical trial, not only to assure safety and health of the trial subjects, but also to provide an exact template for trial conduct by investigators at multiple locations (in a "multicenter" trial) to perform the study in exactly the same way. This harmonization allows data to be combined collectively as though all investigators (referred to as "sites") were working closely together. The protocol also gives the study administrators (often a contract research organization), as well as the site team of physicians, nurses and clinic administrators, a common reference document for site responsibilities during the trial.
The format and content of clinical trial protocols sponsored by pharmaceutical, biotechnology or medical device companies in the United States, European Union, or Japan have been standardized to follow Good Clinical Practice guidance[15] issued by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).[16] Regulatory authorities in Canada and Australia also follow ICH guidelines. Some journals, e.g. Trials, encourage trialists to publish their protocols in the journal.
Design features
Informed consent
An essential component of initiating a clinical trial is to recruit study subjects following procedures using a signed document called "informed consent".[17] Generally, children participating in clinical trial cannot autonomously provide informed consent, but depending on their age and other factors, may be required to provide informed assent.Informed consent is a legally defined process of a person being told about key facts involved in a clinical trial before deciding whether or not to participate. To fully describe participation to a candidate subject, the doctors and nurses involved in the trial explain the details of the study using terms the person will understand. Foreign language translation is provided if the participant's native language is not the same as the study protocol.
The research team provides an informed consent document that includes trial details, such as its purpose, duration, required procedures, risks, potential benefits and key contacts. The participant then decides whether or not to sign the document in agreement. Informed consent is not an immutable contract, as the participant can withdraw at any time without penalty.
Statistical power
The number of patients enrolled in a study has a large bearing on the ability of the study to reliably detect the size of the effect of the study intervention. This is described as the "power" of the trial. The larger the sample size or number of participants in the trial, the greater the statistical power.However, in designing a clinical trial, this consideration must be balanced with the fact that more patients make for a more expensive trial. The power of a trial is not a single, unique value; it estimates the ability of a trial to detect a difference of a particular size (or larger) between the treated (tested drug/device) and control (placebo or standard treatment) groups. By example, a trial of a lipid-lowering drug versus placebo with 100 patients in each group might have a power of 0.90 to detect a difference between patients receiving study drug and patients receiving placebo of 10 mg/dL or more, but only have a power of 0.70 to detect a difference of 5 mg/dL.
Placebo groups
Main article: Placebo-controlled studies
Merely giving a treatment can have nonspecific effects, and these are
controlled for by the inclusion of a placebo group. Subjects in the
treatment and placebo groups are assigned randomly
and blinded as to which group they belong. Since researchers can behave
differently to subjects given treatments or placebos, trials are also
doubled-blinded so the researchers do not know to which group a subject
is assigned.Assigning a person to a placebo group can pose an ethical problem if it violates his or her right to receive the best available treatment. The Declaration of Helsinki provides guidelines on this issue.
Phases
Main article: Phases of clinical research
Clinical trials involving new drugs are commonly classified into four
phases. Each phase of the drug approval process is treated as a
separate clinical trial. The drug-development process will normally
proceed through all four phases over many years. If the drug
successfully passes through Phases 0, 1, 2, and 3, it will usually be
approved by the national regulatory authority for use in the general
population.- Phase 0: Pharmacodynamics and Pharmacokinetics
- Phase 1: Screening for safety
- Phase 2: Establishing the efficacy of the drug, usually against a placebo
- Phase 3: Final confirmation of safety and efficacy
- Phase 4: Sentry studies during sales
In Phase 0 trials are the first-in-human trials. Single subtherapeutic doses of the study drug are given to a small number of subjects (10 to 15) to gather preliminary data on the agent's pharmacodynamics (what the drug does to the body) and pharmacokinetics (what the body does to the drugs).[18]
In Phase 1 trials, researchers test an experimental drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
In Phase 2 trials, the experimental treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.
In Phase 3 trials, the treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow it to be used safely.
In Phase 4 trials, postmarketing studies delineate additional information, including the treatment's risks, benefits, and optimal use.
Before pharmaceutical companies start clinical trials on a drug, they conduct extensive preclinical studies.
Length
Clinical trials are only a small part of the research that goes into developing a new treatment. Potential drugs, for example, first have to be discovered, purified, characterized, and tested in labs (in cell and animal studies) before ever undergoing clinical trials. In all, about 1,000 potential drugs are tested before just one reaches the point of being tested in a clinical trial.[citation needed] For example, a new cancer drug has, on average, six years of research behind it before it even makes it to clinical trials. But the major holdup in making new cancer drugs available is the time it takes to complete clinical trials themselves. On average, about eight years pass from the time a cancer drug enters clinical trials until it receives approval from regulatory agencies for sale to the public.[19] Drugs for other diseases have similar timelines.Some reasons a clinical trial might last several years:
- For chronic conditions such as cancer, it takes months, if not years, to see if a cancer treatment has an effect on a patient.
- For drugs that are not expected to have a strong effect (meaning a large number of patients must be recruited to observe 'any' effect), recruiting enough patients to test the drug's effectiveness (i.e., getting statistical power) can take several years.
- Only certain people who have the target disease condition are eligible to take part in each clinical trial. Researchers who treat these particular patients must participate in the trial. Then they must identify the desirable patients and obtain consent from them or their families to take part in the trial.
For clinical trials involving a seasonal indication (such as airborne allergies, seasonal affective disorder, influenza, and others), the study can only be done during a limited part of the year (such as spring for pollen allergies), when the drug can be tested. This can be an additional complication on the length of the study, yet proper planning and the use of trial sites in the Southern, as well as the Northern Hemisphere allows for year-round trials, which can reduce the length of the studies.[21][22]
Clinical trials that do not involve a new drug usually have a much shorter duration. (Exceptions are epidemiological studies, such as the Nurses' Health Study.
Administration
Clinical trials designed by a local investigator, and (in the US) federally funded clinical trials, are almost always administered by the researcher who designed the study and applied for the grant. Small-scale device studies may be administered by the sponsoring company. Clinical trials of new drugs are usually administered by a contract research organization (CRO) hired by the sponsoring company. The sponsor provides the drug and medical oversight. A CRO is contracted to perform all the administrative work on a clinical trial. For Phases 2, 3 and 4, the CRO recruits participating researchers, trains them, provides them with supplies, coordinates study administration and data collection, sets up meetings, monitors the sites for compliance with the clinical protocol, and ensures the sponsor receives data from every site. Specialist site management organizations can also be hired to coordinate with the CRO to ensure rapid IRB/IEC approval and faster site initiation and patient recruitment. Phase 1 clinical trials of new medicines are often conducted in a specialist clinical trial clinic, with dedicated pharmacologists, where the subjects can be observed by full-time staff. These clinics are often run by a CRO which specialises in these studies.At a participating site, one or more research assistants (often nurses) do most of the work in conducting the clinical trial. The research assistant's job can include some or all of the following: providing the local institutional review board (IRB) with the documentation necessary to obtain its permission to conduct the study, assisting with study start-up, identifying eligible patients, obtaining consent from them or their families, administering study treatment(s), collecting and statistically analyzing data, maintaining and updating data files during followup, and communicating with the IRB, as well as the sponsor and CRO.
Ethical conduct
Main articles: Clinical research ethics and Clinical trials publication
Clinical trials are closely supervised by appropriate regulatory
authorities. All studies involving a medical or therapeutic intervention
on patients must be approved by a supervising ethics committee
before permission is granted to run the trial. The local ethics
committee has discretion on how it will supervise noninterventional
studies (observational studies or those using already collected data).
In the US, this body is called the Institutional Review Board
(IRB). Most IRBs are located at the local investigator's hospital or
institution, but some sponsors allow the use of a central
(independent/for profit) IRB for investigators who work at smaller
institutions.To be ethical, researchers must obtain the full and informed consent of participating human subjects. (One of the IRB's main functions is to ensure potential patients are adequately informed about the clinical trial.) If the patient is unable to consent for him/herself, researchers can seek consent from the patient's legally authorized representative. In California, the state has prioritized the individuals who can serve as the legally authorized representative.[23]
In some US locations, the local IRB must certify researchers and their staff before they can conduct clinical trials. They must understand the federal patient privacy (HIPAA) law and good clinical practice. The International Conference of Harmonisation Guidelines for Good Clinical Practice is a set of standards used internationally for the conduct of clinical trials. The guidelines aim to ensure the "rights, safety and well being of trial subjects are protected".
The notion of informed consent of participating human subjects exists in many countries all over the world, but its precise definition may still vary.
Informed consent is clearly a 'necessary' condition for ethical conduct but does not 'ensure' ethical conduct. The final objective is to serve the community of patients or future patients in a best-possible and most responsible way. However, it may be hard to turn this objective into a well-defined, quantified, objective function. In some cases this can be done, however, for instance, for questions of when to stop sequential treatments (see Odds algorithm), and then quantified methods may play an important role.
Additional ethical concerns are present when conducting clinical trials on children (pediatrics).
Commercial ties and unfavorable studies
Due to repeated accusations and findings that some clinical trials conducted or funded by pharmaceutical companies may report only positive results for the preferred medication, the industry has been looked at much more closely by independent groups and government agencies.[24]In response to specific cases in which unfavorable data from pharmaceutical company-sponsored research was not published, the Pharmaceutical Research and Manufacturers of America have published new guidelines urging companies to report all findings and limit the financial involvement in drug companies of researchers.[25] US congress signed into law a bill which requires phase II and phase III clinical trials to be registered by the sponsor on the clinical trials website run by the NIH.[26]
Drug researchers not directly employed by pharmaceutical companies often look to companies for grants, and companies often look to researchers for studies that will make their products look favorable. Sponsored researchers are rewarded by drug companies, for example with support for their conference/symposium costs. Lecture scripts and even journal articles presented by academic researchers may actually be 'ghost-written' by pharmaceutical companies.[27] Some researchers who have tried to reveal ethical issues with clinical trials or who tried to publish papers that show harmful effects of new drugs or cheaper alternatives have been threatened by drug companies with lawsuits.[28][29]
Safety
Responsibility for the safety of the subjects in a clinical trial is shared between the sponsor, the local site investigators (if different from the sponsor), the various IRBs that supervise the study, and (in some cases, if the study involves a marketable drug or device), the regulatory agency for the country where the drug or device will be sold.For safety reasons, many clinical trials of drugs are designed to exclude women of childbearing age, pregnant women, and/or women who become pregnant during the study. In some cases, the male partners of these women are also excluded or required to take birth control measures.
Sponsor
Throughout the clinical trial, the sponsor is responsible for accurately informing the local site investigators of the true historical safety record of the drug, device or other medical treatments to be tested, and of any potential interactions of the study treatment(s) with already approved medical treatments. This allows the local investigators to make an informed judgment on whether to participate in the study or not. The sponsor is also responsible for monitoring the results of the study as they come in from the various sites, as the trial proceeds. In larger clinical trials, a sponsor will use the services of a data monitoring committee (DMC, known in the US as a data safety monitoring board). This independent group of clinicians and statisticians meets periodically to review the unblinded data the sponsor has received so far. The DMC has the power to recommend termination of the study based on their review, for example if the study treatment is causing more deaths than the standard treatment, or seems to be causing unexpected and study-related serious adverse events.The sponsor is responsible for collecting adverse event reports from all site investigators in the study, and for informing all the investigators of the sponsor's judgment as to whether these adverse events were related or not related to the study treatment. This is an area where sponsors can slant their judgment to favor the study treatment.The sponsor and the local site investigators are jointly responsible for writing a site-specific informed consent that accurately informs the potential subjects of the true risks and potential benefits of participating in the study, while at the same time presenting the material as briefly as possible and in ordinary language. FDA regulations and ICH guidelines both require "the information that is given to the subject or the representative shall be in language understandable to the subject or the representative." If the participant's native language is not English, the sponsor must translate the informed consent into the language of the participant.[30]
Local site investigators
A physician's first duty is to his/her patients, and if a physician investigator believes the study treatment may be harming subjects in the study, the investigator can stop participating at any time. On the other hand, investigators often have a financial interest in recruiting subjects, and can act unethically to obtain and maintain their participation.The local investigators are responsible for conducting the study according to the study protocol, and supervising the study staff throughout the duration of the study. The local investigator or his/her study staff are also responsible for ensuring the potential subjects in the study understand the risks and potential benefits of participating in the study; in other words, they (or their legally authorized representatives) must give truly informed consent. They are responsible for reviewing all adverse event reports sent by the sponsor. (These adverse event reports contain the opinion of both the investigator at the site where the adverse event occurred, and the sponsor, regarding the relationship of the adverse event to the study treatments). They also are responsible for making an independent judgment of these reports, and promptly informing the local IRB of all serious and study treatment-related adverse events.
When a local investigator is the sponsor, there may not be formal adverse event reports, but study staff at all locations are responsible for informing the coordinating investigator of anything unexpected. The local investigator is responsible for being truthful to the local IRB in all communications relating to the study.
Institutional review boards (IRBs)
Approval by an Institutional Review Board (IRB), or ethics board, is necessary before all but the most informal medical research can begin. In commercial clinical trials, the study protocol is not approved by an IRB before the sponsor recruits sites to conduct the trial. However, the study protocol and procedures have been tailored to fit generic IRB submission requirements. In this case, and where there is no independent sponsor, each local site investigator submits the study protocol, the consent(s), the data collection forms, and supporting documentation to the local IRB. Universities and most hospitals have in-house IRBs. Other researchers (such as in walk-in clinics) use independent IRBs.The IRB scrutinizes the study for both medical safety and protection of the patients involved in the study, before it allows the researcher to begin the study. It may require changes in study procedures or in the explanations given to the patient. A required yearly "continuing review" report from the investigator updates the IRB on the progress of the study and any new safety information related to the study.
Regulatory agencies
If a clinical trial concerns a new regulated drug or medical device (or an existing drug for a new purpose), the appropriate regulatory agency for each country where the sponsor wishes to sell the drug or device is supposed to review all study data before allowing the drug/device to proceed to the next phase, or to be marketed. However, if the sponsor withholds negative data, or misrepresents data it has acquired from clinical trials, the regulatory agency may make the wrong decision. However, if leaders of the regulatory agency are friendly to industry, they may pressure staff scientists to make decisions favorable to industry, disregard their findings, or make it otherwise difficult for them to do their job.[31]In the US, the FDA can audit the files of local site investigators after they have finished participating in a study, to see if they were correctly following study procedures. This audit may be random, or for cause (because the investigator is suspected of fraudulent data). Avoiding an audit is an incentive for investigators to follow study procedures.
Alternatively, many American pharmaceutical companies have moved their clinical trials overseas. By doing this they are able to avoid many of the FDA’s regulations, since the FDA rarely investigates clinical trials outside the United States. This increases the ability of pharmaceutical companies to skew results obtained overseas in order to make a profit. [32]
Different countries have different regulatory requirements and enforcement abilities. An estimated 40% of all clinical trials now take place in Asia, Eastern Europe, and Central and South America. "There is no compulsory registration system for clinical trials in these countries and many do not follow European directives in their operations", says Dr. Jacob Sijtsma of the Netherlands-based WEMOS, an advocacy health organisation tracking clinical trials in developing countries.[33]
Beginning in the 1980s, harmonization of clinical trial protocols was shown as feasible across countries of the European Union. At the same time, coordination between Europe, Japan and the United States led to a joint regulatory-industry initiative on international harmonization named after 1990 as the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)[34] Currently, most clinical trial programs follow ICH guidelines, aimed at "ensuring that good quality, safe and effective medicines are developed and registered in the most efficient and cost-effective manner. These activities are pursued in the interest of the consumer and public health, to prevent unnecessary duplication of clinical trials in humans and to minimize the use of animal testing without compromising the regulatory obligations of safety and effectiveness."[35]
