Independent clinical trial

Clinical trials are medical research studies that involve volunteers - both healthy and ill people - in order to test treatments for preventing, detecting or curing diseases.
Why is clinical research so important?
Opinions, even the most authoritative, and habits are not enough for deciding if a certain treatment is going to benefit patients and if the benefits will outweigh adverse reactions.
Without fair - unbiased - evaluations, useless or even harmful treatments may be prescribed because they are thought to be helpful or, conversely, helpful treatments may be dismissed as useless. Untested theories about treatment effects, however convincing they may sound, are just not enough. Some theories have predicted that treatments would work, but fair tests have revealed otherwise; other theories have confidently predicted that treatments would not work when, in fact, tests showed that they did.
Although there is a natural tendency to think that ‘new’ means ‘improved’, when new treatments are assessed in fair tests they are just as likely to be found worse as they are to be found better than existing treatments. There is an equally natural tendency to think that, because something has been around for a long time, it must be safe and it must be effective. But healthcare is littered with the use of treatments that are based on habit or firmly held beliefs rather than evidence: treatments that often do not do any good and sometimes do substantial harm. It is also important to know that people often recover from illness without any specific treatment, and that the ‘natural’ progress and outcome of illnesses without treatment must be taken into account when treatments are being tested.
Healthcare systems nowadays require sound scientific evidence on effectiveness and safety before allowing the marketing of a new treatment, medical device, diagnostic or surgical procedure especially when, as it happens in the EU, they cover the costs in total or partially for citizens. The only way to make sure large amounts of money are not wasted in useless or even harmful treatments while effective ones are neglected is to wait for the results of well-designed clinical trials.
Clinical trials can have a variety of sponsors such as pharmaceutical industries, government, research charities, foundations, medical institutions and voluntary groups like patients’ associations. Clinical trials are “independent” if they are funded by public money, research centres or voluntary groups such as patients’ associations. These trials should primarily aim at addressing issues of main interest for the patients (for example, investigating long-term risks and rare adverse reactions of a treatment, comparing the available therapeutic options or evaluating the improvements in the quality of life) in treatments that are of no commercial interest but nevertheless potentially important. On the other hand, the majority of clinical trials today are sponsored by pharmaceutical industries and most of them aim at demonstrating effectiveness and safety of a new treatment for the approval by regulators.
What is an independent clinical trial?
Clinical trials can have a variety of sponsors such as pharmaceutical industries, government, research charities, foundations, medical institutions and voluntary groups like patients’ associations. Clinical trials are “independent” if they are funded by public money, research centres or voluntary groups such as patients’ associations. These trials should primarily aim at addressing issues of main interest for the patients (for example, investigating long-term risks and rare adverse reactions of a treatment, comparing the available therapeutic options or evaluating the improvements in the quality of life) in treatments that are of no commercial interest but nevertheless potentially important. On the other hand, the majority of clinical trials today are sponsored by pharmaceutical industries and most of them aim at demonstrating effectiveness and safety of a new treatment for the approval by regulators.
Independent clinical trials are of critical importance for improving the effectiveness, safety, and cost-effectiveness of healthcare. They also help establishing the relative efficacy of interventions, and thus their position in the therapeutic armamentarium, and they foster affordability for the health services. They promote comparisons of treatment options (drug and non-drug) for a given health problem. This meets the expectations of patients, healthcare professionals, and health systems, to whom the relevant question is “what is the best treatment option for this problem?” rather than “is this particular product effective and safe?”
Most drug and device clinical trials are sponsored by the pharmaceutical industry, working in close collaboration with academic investigators and clinicians. These trials are product-oriented, aimed at providing evidence for the benefits of a given product (does this product merit a marketing authorization?). However, a very large number of clinical research questions are of little or no interest to commercial sponsors, yet they need to be addressed because of their importance in promoting the health of the public and improving diagnosis and therapy for large, medium-sized, and small patient groups. This large number of clinical research questions deals not only with drugs and devices, but also with new biomedical interventions, surgery, physiotherapy, psychology, rehabilitation, training, etc. Such healthcare-oriented research questions (what is the best therapeutic option for this disease, this patient or this group of patients?) are clearly critical for patients, healthcare professionals, healthcare systems, reimbursement policies and payers. They are usually addressed through the initiative of clinical investigators or patient groups. Investment in independent assessments of treatment strategies has a highly positive return on society in terms of decreases in the burden of disease, increased productivity due to optimized healthcare strategies, and cost containment in healthcare systems.
Uncertainty in research
The most that research can usually do is to chip away at the uncertainties. Treatments can be harmful as well as helpful. Good, well-conducted research can indicate the probability (or likelihood) that a treatment for a health problem will lead to benefit or harm by comparing it with another treatment or no treatment at all. Since there are always uncertainties it helps if we try to avoid the temptation to see things in black and white. And thinking in terms of probabilities is empowering. People need to know the likelihood of a particular outcome of a condition - say stroke in someone with high blood pressure - the factors that affect the chance of a stroke happening, and the probability of a treatment changing the chances of a stroke happening. With enough reliable information, patients and health professionals can then work together to assess the balance between the benefits and harms of treatments. They can then choose the option that is likely to be most appropriate according to individual circumstances and patient preferences.
Conflicts of interest
A conflict of interest occurs when an individual or organization is involved in multiple interests, one of which could possibly corrupt the motivation for an act in another.
The presence of a conflict of interest is independent from the execution of impropriety. Therefore, a conflict of interest can be discovered and voluntarily defused before any corruption occurs. A widely used definition is: "A conflict of interest is a set of circumstances that creates a risk that professional judgement or actions regarding a primary interest will be unduly influenced by a secondary interest." Primary interest refers to the principal goals of the profession or activity, such as the protection of clients, the health of patients, the integrity of research, and the duties of public office. Secondary interest includes not only financial gain but also such motives as the desire for professional advancement and the wish to do favours for family and friends, but conflict of interest rules usually focus on financial relationships because they are relatively more objective, fungible, and quantifiable. The secondary interests are not treated as wrong in themselves, but become objectionable when they are believed to have greater weight than the primary interests. The conflict in a conflict of interest exists whether or not a particular individual is actually influenced by the secondary interest. It exists if the circumstances are reasonably believed (on the basis of past experience and objective evidence) to create a risk that decisions may be unduly influenced by secondary interests.
What about conflict of interest in clinical trials?
When researchers or doctors who are conducting clinical trials or recommending patients to be volunteers receive money from the pharmaceutical companies that produce the treatments being tested, potential conflicts of interest arise. Since the monetary gain may affect the results of the studies, all the most prestigious medical journals require and publish a conflicts of interest declaration in the footnote of every article about clinical trials.
Disclosure of conflict of interest
Public trust in the scientific process and the credibility of published articles depend in part on how transparently conflicts of interest are handled during the planning, implementation, writing, peer review, editing, and publication of scientific work. Financial relationships (such as employment, consultancies, stock ownership or options, honoraria, patents, and paid expert testimony) are the most easily identifiable conflicts of interest and the most likely to undermine the credibility of the journal, the authors, and of science itself. However, conflicts can occur for other reasons, such as personal relationships or rivalries, academic competition, and intellectual beliefs. Agreements between authors and study sponsors that interfere with the authors’ access to all of a study’s data or that interfere with their ability to analyze and interpret the data and to prepare and publish manuscripts independently may represent conflicts of interest, and should be avoided. All participants in the publication process must consider their conflicts of interest when fulfilling their roles in the process of article review and publication and must disclose all relationships that could be viewed as potential conflicts of interest.
Are there different types of clinical trials?
One way of classifying clinical trials is by the way the researchers behave.
In an interventional study, the investigators give the research subjects a particular treatment. Usually, they compare the treated subjects to subjects who receive no treatment or standard treatment. Then the researchers measure how the subjects' health changes. Randomized clinical trials are interventional studies, considered the most reliable instruments for gathering information about treatments effectiveness and safety since they allow researchers to minimize possible confounding factors (bias).
However, setting up a randomized clinical trial is not always possible, sometimes for ethical reasons but in other cases because of costs and long time required or the type of question the trial is designed to address.
Depending on the type of questions the research team wants to answer, then, clinical trials can be classified as:
* Prevention trials look for better ways to prevent disease in people who have never had the disease or to prevent a disease from returning. These approaches may include drugs, vaccines or lifestyle changes.
* Screening trials test the best way to detect certain diseases or health conditions.
* Diagnostic trials are conducted to find better tests or procedures for diagnosing a particular disease or condition.
* Treatment trials test experimental treatments, new combinations of drugs or new approaches to surgery or radiation therapy. Some trials assess the quality of life as an outcome.

In an observational study, the investigators observe the subjects and measure their outcomes. Participants are “followed”, observed sometimes over years to understand more about risk factors, possible effects of exposure to certain substances, life styles, etc… Even though observational studies are potentially more subject to bias because participants are not assigned randomly to groups, they nevertheless can provide valuable information about everyday practice, potential risk factors or safety issues, which then can be investigated in further clinical trials if feasible.
Key words of clinical trials
* Randomization is a methodology that casually allocates the study participants to one treatment group or another. It helps setting similar groups, so that, when their results are compared at the end, differences are known to be due to the given interventions and not to pre-existing differences. In fact, previous existing conditions or differences among the patients could affect the study results. When only one treatment is under investigation, the patients receiving it are said to be in the “active” group, while the others (who receive a dummy treatment - a placebo - or an already tested one) are in the “control” group. These are randomized controlled trials and patients are assigned by chance, like tossing a coin, to the active or to the control group.
* Comparisons are key to all fair tests of treatments. Treatments are usually tested by comparing groups of patients who have received different treatments. If treatment comparisons are to be fair, comparisons must ensure that like will be compared with like and that the only systematic difference between the groups of patients is the treatments they have received. The comparison should be made with the best treatment available.
* Blinded-Masking. When patients in the active and control groups do not know which group they are in - therefore ignoring the treatment they are taking, (the active/new one or the dummy/standard one?) - the study is said to be “single masked”, often still referred to as “single blinded”, even this term is now considered less appropriated. If also the doctors who are administering the treatments do not know who is taking what, the study is “double masked”, again, often called “double blinded”. Masking avoid patients and researchers to get influenced when observing good and negative effects of the treatment. If a physician knew which patient was getting the study treatment and which patient was getting the placebo (or the standard treatment), 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. (Main article: Clinical trial)
* Outcome. A component of a participant's clinical and functional status after an intervention has been applied, that is used to assess the effectiveness of an intervention. Primary: the outcome of greatest importance, for example, reduced mortality in clinical trials about infarction. Secondary: an outcome used to evaluate additional effects of the intervention, deemed a priori as being less important than the primary outcomes.
The primary outcome of a clinical trial assessing the effects of a drug in preventing mortality is overall mortality. If other analysis are conducted, for example assessing the frequency of non fatal infarctions, these are secondary outcomes. Secondary outcomes should only be used as further information supporting the conclusions coming out from the primary outcome analysis, or to raise research hypothesis/questions.
Surrogate outcome: are often used as proxies for hard primary clinical outcomes. For instance, cholesterol is used as a surrogate outcome for a reduction in mortality.
The critical point is that the beneficial effects of a treatment on surrogate outcomes (for example, reduction in cholesterol levels) do not automatically imply health benefits, that is, reduced mortality for infarction). Many drugs, approved on the basis of surrogate outcome data, were shown to be harmful after their use in clinical practice.
What are pre-clinical studies?
Also known as laboratory studies, these are the first necessary steps in making of a new treatment before testing it on people. Pre-clinical studies include cell-studies and animal testing. Developing new treatments is often a very long process, which usually takes years: tests in the laboratory and on animals are often necessary before researchers can involve volunteers in a clinical trial.
What happens during a clinical trial?
In order to answer a clinical question, the research team defines a clinical trial protocol with all the relevant details of the study, which needs the approval of competent authorities, an Institutional Review Board (also known as Independent Research Ethics Committee).
The process depends on what type of clinical trial you might be considering. For example clinical trials for assessing whether a new treatment should be approved will firstly assess if it can harm patients, secondly whether it works, and finally compare it with already existing treatments (or placebo) to find out which works better.
Studies are conducted in universities, medical centres, clinics, hospitals or even doctor’s offices.
Clinical trials are called “multicentre” when several clinical centres are involved. The benefits of multicenter trials include a larger number of participants, different geographic locations, the possibility of inclusion of a wider range of population groups, and the ability to compare results among centres, all of which increase the generalizability of the study. In multicenter trial the expected number of patients needed for the study is reached faster than in single-centre trials
What are the phases of clinical trials testing a new drug?
The clinical trial process is very rigorous and usually consists of 4 different phases, if the researchers are testing a new drug. Each phase has a different purpose, helps the research team to address different questions about the treatment and implies different risks and benefits for you. The process described below is typical of new drug development.
* Phase I trials - Is it sufficiently safe to proceed?
This phase uses low up to therapeutic doses of a new experimental treatment on a small group of people (20-80) in order to evaluate its safety and identify adverse effects.
Phase 1 studies attempt to find the highest dose of the new treatment that can be given without serious adverse effects. These studies also help to decide on the best way to give the new treatment.
This phase does not identify rare adverse reactions since it involves only a small number of patients. This is potentially the most risky phase for the participants.
* Phase II trials - Is there evidence of potential beneficial effects?
In this phase, the new treatment is administered to a larger group of people (100-300) to investigate its hoped-for beneficial effects and further evaluate its safety. The researchers look for some evidence that the treatment works and keep watching the patients closely for any adverse reaction. Less common adverse effects should become more evident since the number of participants will have increased.
* Phase III trials - Is it better?
If a new treatment “passes” phase II, then it is finally tested on large groups of people (typically 1,000-3,000), usually in different research centres. At this point effectiveness and safety are not enough, the new treatment must show to be better than the standard treatment, i.e. it must provide more benefits or fewer risks for the patients than what is already in use. If the results of the study are positive and the research team collects evidence of effectiveness from two different phases 3 studies, they can apply for a marketing authorization to the competent authority. In EU this is the European Medicines Agency, but there are also National Agencies in each Member State. For ethical reason, giving a placebo is unethical if there is already another known beneficial treatment.
* Phase IV trials - What else?
Rare and potentially severe adverse effects of a new treatment - but also benefits in the usual clinical practice - may be hard to detect, even after the new treatment has been used by thousands of patients. For this reason, researchers often continue collecting information about benefits, risks and optimal use after a drug has been approved for marketing and is available to the public.

Transparency in research
Doctors and regulators need the results of clinical trials to make informed decisions about treatments. But companies and researchers can withhold the results of clinical trials even when asked for them. The best available evidence shows that about half of all clinical trials have never been published, and trials with negative results about a treatment are much more likely to be brushed under the carpet.
The Declaration of Helsinki, which is the World Medical Association’s statement of principles for medical research involving people, states that every investigator running a clinical trial should register it and report its results. Millions of volunteers have participated in clinical trials to help find out more about the effects of treatments on disease, yet that important ethical principle about reporting has been widely ignored. Information on what was done and what was found in these trials could be lost forever to doctors and researchers, leading to bad treatment decisions, missed opportunities for good medicine, and trials being repeated. This is a serious problem for evidence based medicine because all the evidence about a treatment is needed to understand its risks and benefits.
This is what led to the AllTrials campaign in January 2013, a campaign which is now supported by thousands of individual patients, clinicians and researchers across the world, and by hundreds of organisations representing millions of people. The AllTrials campaign is an initiative of Bad Science, BMJ, Centre for Evidence-based Medicine, Cochrane Collaboration, James Lind Initiative, PLOS and Sense About Scienceand is being led in the US by Dartmouth’s Geisel School of Medicine and the Dartmouth Institute for Health Policy & Clinical Practice. The AllTrials initiative is campaigning for the publication of the results (that is, full clinical study reports) from all clinical trials - past, present and future - on all treatments currently being used. The campaign supporters are calling on governments, regulators and research bodies to implement measure to achieve this. And they are also calling for all universities, ethics committees and medical bodies to enact a change of culture, recognise that underreporting of trials is misconduct and police their own members to ensure compliance.
The European Medicines Agency leads the way to the publication and access to clinical trial data
The European Medicines Agency (EMA) has released a draft policy on the publication and access to clinical-trial data. The Agency has committed to the proactive publication of data from clinical trials submitted in support of a marketing-authorisation application, once the decision-making process has ended. In its draft policy, the Agency has defined three categories of clinical-trial data corresponding to different levels of access.
* Clinical-trial data, information or documents that do not contain patients’ personal data. This information will be freely available and downloadable from the Agency’s website.
* Clinical-trial data, information or documents containing patients’ personal data. Requiring researchers can have a restricted access to these information. Two levels of protection are foreseen to provide best-possible assurance against retroactive patient identification. Firstly, data will need to be adequately de-identified. Secondly, access to these data will only be granted after the requester has fulfilled a number of requirements. In this way, other researchers - different from those conducting the study - can have access to these data and make other analysis.
* Clinical-trial data, information or documents that may contain commercially confidential information. These are considered commercially confidential information, not available.
In June 2013 EMA opened a three-month public consultation, a range of different stakeholders sent more than 1,000 observations.
In June 2014 the Management Board meeting agreed the policy on publication of clinical trial data, final documents should be ready by mid-July 2014.
The European Ombudsman has expressed several concerns about the changes made during the development of the last version of the document discussed in June 2014.
The European Parliament and clinical trials
On 2 April 2014 the European Parliament approved the new Clinical Trials Regulations with 594 votes in favour, 17 against and 13 abstentions. As underlined in the official press release: “The new Regulation will make it easier to conduct multinational clinical trials, i.e. conducted in more than one Member State, in the EU. Measures that cut red tape and simplify the current rules are:
* A straightforward authorization procedure allowing for a fast and thorough assessment of the application by all Member States concerned and resulting in one single assessment outcome. The authorization procedure allows the individual EU countries to determine the roles of the bodies in charge of the assessment, on the condition that the assessment is fully independent and based on the necessary expertise.
* Simplified reporting procedures so that researchers no longer have to submit largely identical information on the clinical trial separately to various bodies and Member States.
* The possibility for the Commission to conduct controls in EU countries and third countries to make sure the rules are being properly supervised and enforced.
Finally, the new legislation will take the legal form of a Regulation. This will ensure that the rules for conducting clinical trials are identical throughout the EU. This is vital to ensure that Member States, in authorizing and supervising the conduct of a clinical trial, base themselves on identical rules.
Moreover, some problematic issues are underlined as reported in British Medical Journal (Westra AE, Bos W, Cohen AF. New EU clinical trials regulation. BMJ 2014;348:g3710). In particular, as the new regulation requests two assessments - one coordinate risk-benefit assessment by one member state binding on all member states, and one local assessment mainly for informed consent and feasibility - concerns are expressed about the quality of the judgments, and the lack of requirements for Ethical Committees in the EU Clinical Trials Regulations.
The promoters of the All trials campaign appreciated that Europe votes for clinical trial transparency. Some aspects of the new EU regulation are very important in order to guarantee the citizens, patients and researchers have access to the results of clinical trials. In particular: the request of registration on the publicly accessible EU clinical trials register (set up and run by the European Medicines Agency), the publication within 12 months of the end of the study of the summary of results understandable also to a lay person, financial penalties on anyone running a clinical trial who does not adhere to these new laws. Unfortunately these new rules for transparency are not retrospective.
Pitfalls and traps
Pitfalls can arise in evaluating if a treatment is effective. For example, although high levels of cholesterol are a risk factor for myocardial infarction, a new treatment aimed at reducing cholesterol cannot be considered effective in preventing myocardial infarction unless it reduces mortality. Simply reducing cholesterol is not enough. A treatment must be evaluated for its ability to improve outcomes that are important to patients.
So that the research results can be confidently used to guide practice, a trial must include patients for whom the treatment is intended. Children, elderly people, ethnic minorities and women are too frequently excluded from research.
There may be shortcomings in the design of clinical trials. The aim is not just to decide whether a new treatment is as effective as the current standard treatment through non-inferiority trials. Clinical trials must be designed to show whether a proposed new treatment is better than an existing treatment. Patients want to know whether a new treatment is actually better, not just the same or simply no worse.
It is not enough that the new treatment is shown to be more effective than the control. It must really improve patient’s health, so its benefits and risks must be carefully evaluated - to be sure that the pros outweigh any cons.
The informed consent
The informed consent is a procedure by which a subject voluntarily agrees to participate in a clinical study after being informed of their health condition, of all the methodological and practical aspects of the study, expected risks and benefits.
The informed consent must to be clear, simple, short, acronyms or technical terms should be avoid, all the medical terms should be clearly explained.
Informed consent is documented by means of a form that must be signed and dated by the subject himself.
The informed consent recognizes the need to know about a procedure, surgery, or treatment, before the decision whether to have it. Doctors and nurses have an important role in the process of the informed consent: they must present and discuss the study to the patients and be sure that patient understands the purpose, the benefits and risks, and the all procedures of the clinical trial.
The patient must be guaranteed:
* a complete information about all benefits and risks, and the nature of the study
* the chance to refuse to enter the study, however, getting the best available care
* the chance to ask questions about the study, and to share the decision with doctor and researchers team
* the time to discuss about the study with family, friends or others physicians
* the opportunity to withdraw from the study in any moment without explanations
* the confidentiality of the data collected
If any collection of biological material or genetic testing is required, the patient must receive complete information about use and conservation process. Specific informed consent should be required for that purpose.
It is the patient who must give consent to participate; particular cases are represented by minors, subjects not able to express a consent, subjects in emergency condition. Each country developed specific norms for these cases.
Multicentre clinical trials
Multicentre (and multi-investigator) clinical trials are those conducted in two or more centre. Multicentre clinical trials are considered more efficient because the enrolling process of subjects is facilitate, allowing to satisfy the trial objective in a reasonable time, and because of the generalizability of the results. Multicentre clinical trials need much effort in term of co-ordination, quality control, and data management.
Acknowledgments
The ECRAN partners involved in this task kindly thank Marien Gonzalez Lorenzo, Clinical Epidemiology Unit, IRCCS Galeazzi Orthopedic Institute; Department of Biomedical Sciences for Health, UNIMI, Milano; Ann-Isabelle von Lingen, EATG Policy Officer for their precious help in the review of pages in Spanish and French.

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