Clinical Trials Explained What is the process and what does it mean to participate?

Transcription

1 Clinical Trials Explained What is the process and what does it mean to participate? Co-funded by the Seventh Framework Programme of the European Union

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3 How new therapies are developed From initial discovery through to launch, a new therapy goes through several different stages of development. The first step in discovery of a potential drug, gene or cell therapy is where scientists select a therapeutic concept such as a gene or protein that plays a key role in the medical condition that is being investigated. Many hundreds of drug candidates will typically be tested to find one molecule or compound that can act on this target to reduce symptoms or alter the condition. In the case of a cell or a gene therapy the cell or gene is optimised for a desired function. In the preclinical stage, early tests of a therapy s safety and effectiveness are carried out. This initial testing involves two types of studies: In vitro studies performed in test tubes often using screening on human or animal cells In vivo studies that look at the effects of the therapy in animals One or two selected drug candidates undergo rigorous testing with the purpose to establish a dose that can be safely tested in humans. The same rigorous principles apply even if the therapeutic is not a drug, but an implantable cell or a gene. After safety has been confirmed, a potential new therapy will then go through a series of clinical trials starting in healthy volunteers and moving on to people with the condition under treatment. These start off as small studies and become larger and more complicated as a therapy is tested through the development process. When all clinical trials are complete, the information and results are collected together and submitted to the regulatory agency for licensing approval. Once a therapy has been approved by the regulators it is licensed for use and becomes available to patients on prescription as a new treatment. 3

4 The purpose of clinical trials Clinical trials help to develop an understanding of how a new therapy works in humans. Clinical trials might ask a participant to take an experimental new therapy, receive an implant, test a device and/or undergo surgery. The data collected from clinical trials can be used to answer five key questions about a new therapy: Does it have the desired therapeutic effect to help treat or improve the symptoms of the condition? How does it compare to other therapies already used to treat that condition? What is the best dose to use to give the best effectiveness with the lowest risk of side effects? Is it as safe as possible? What are the main side effects? 4 Different phases of clinical trials A new therapy goes through three different phases of clinical trials to determine if it is safe and if it works. As positive data on safety and efficacy are collected, trials gather momentum and the number of patients that are enrolled increases. Phase 1 trials are small studies also known as pilot studies carried out in a small number of people, usually between 10 and 100. Their main aim is to test the safety of a new therapy. During phase 1, the potential therapy is typically tested in healthy volunteers and investigators test for side effects and calculates the best dose to use in Phase 2 trials. Because this is the first time the therapy has been tried in humans, investigators start with a very small dose and only increase it if the recipient experiences no significant side effects. Phase 2 trials assess the effectiveness of a new therapy, most often compared to placebo (dummy drug) in a larger pool of patients, usually The goal is to see whether the therapy works, and how effective it is in the short-term. Phase 2 trials always involve people who are living with the condition that the new therapy is intended to treat. Phase 3 trials are large-scale, longer clinical studies that test a new therapy, typically in a thousand or more patients. In phase 3, a new therapy will be compared with currently prescribed therapies or a placebo to see if it works better in clinical practice. Important safety data are also collected in phase 3 to determine if the new therapy has any significant side effects and whether the overall balance of effectiveness

5 and safety the therapy s benefit-risk profile - is favourable. A therapy can only reach phase 3 trials once it has successfully completed phase 1 and 2. Sometimes, when the therapy involves a more invasive procedure, for example, gene or cell therapy, the typical Phase 1/2/3 study structure does not necessarily apply and Phase 1 studies can be conducted in patients. For some advanced therapies intended for relatively rare conditions or a certain subgroup of patients, it is not possible to conduct a large clinical trial with thousands of patients. Phase 4 trials are specific types of clinical studies only carried out after a therapy has been given licensing approval by regulatory authorities for use as an approved treatment. In phase 4 trials, data on the effectiveness and safety (particularly any longer-term side effects) of the therapy continue to be collected while it is used by patients in clinical practice. Not every therapy will be required to go through phase 4 testing. Time to Flourish Inside innovation: the medicine development process The pharmaceutical industry develops 90% of medicines 2 Re-investing profits from medicines enables companies to develop new medicines for patients Average number of years taken to develop successful medicine 2 Average cost to research and develop successful medicine 3 Number of medicinal candidates tested to achieve one approved medicine 4 Pre discovery Based on their disease focus, companies scientists work to understand disease 4-5 years 5.5 years 7.0 years 8.5 years 11.0 years 12.5 years 436 million 533 million 710 million 916 million 1.1 billion 1.15 billion 5,000-10,000 candidates Drug discovery Researchers select a target, such as a gene or protein, then search for a molecule, or compound, that may act on the target to alter the disease candidates Pre-clinical testing Early safety and efficacy tests are undertaken in computational models, cells and in animals 5-10 candidates Phase 1 clinical trial The candidate medicine is tested in people for the first time. Studies are conducted with about 20 to 100 healthy volunteers 2-5 candidates Phase 2 clinical trial Researchers evaluate the candidate medicine s efficacy in about 100 to 500 patients with the disease 1-2 candidates Phase 3 clinical trial Researchers study the candidate medicine in about 1,000 to 5,000 patients to generate data about safety, efficacy and the overall benefit-risk relationship of the medicine 1 medicine Licensing approval Information and results from all the studies is compiled and submitted to the regulatory agencies Medicine available for patients The medicine is now licensed for use and patients may benefit from it, subject to value and cost-effectiveness assessments and local health budget availability

6 Ensuring clinical trials are safe Almost all therapies have side effects. Even therapies which have been available for many years and are used every day in large numbers of patients can sometimes cause problems for some people. Clinical trials are crucial to help us understand the benefits of a new therapy, and weigh that up against the risk of side effects. As a new therapy moves through clinical trials, its benefit-risk profile is continually monitored. Regular reviews of a therapy s safety are carried out by independent Data and Safety Monitoring Boards (DSMBs) who can step in to halt a trial if there are any safety concerns. Although rare, side effects may take several years to appear, in general the safety profile of a new therapy becomes clearer and better understood as more and more patients are treated in clinical trials. A clinical trial cannot take place until an independent ethics committee has given approval for it to go ahead Ensuring clinical trials are fair Clinical trials are designed to be rigorous and unbiased. This objectivity is built into a clinical trial in three key ways: Placebo: A placebo is a dummy therapy designed to look the same as the real therapy. The placebo effect is a powerful phenomenon where a person s symptoms improve, but the effect is not attributable to any real therapy. For example, a patient may feel better after just taking a sugar pill if they expect it to work, or if they have received regular, positive attention from a healthcare professional. To account for the placebo effect, many clinical studies split patients into two groups one group that receives the new therapy being studied and one group that gets placebo. This type of trial is called a placebo-controlled study. Using a placebo group makes it possible to identify the real effects of the therapy, separate from any improvements due to the placebo effect. Testing new therapies against placebo is often a formal requirement in order for a new therapy to become commercially available. Many placebo-controlled studies have an extension trial, which allows all those involved to have the active therapy if they wish. 6

7 Blinding: In a blinded trial, participating patients do not know which therapy they have been allocated to receive. If the trial is double-blind, neither the patient nor the doctors and researchers administering the therapy know who is getting the new therapy and who is receiving the placebo. Double-blind trials are important in reducing the effects of bias when comparing the outcomes from different therapies. Randomisation: In a randomised trial, participants are allocated to one of the therapy groups in the study in a random and unplanned way. This helps to ensure the patients within each group in the trial are similar, and that investigators have no influence over which therapy an individual ultimately receives. Randomisation is usually carried out by a computer. The challenges of clinical trials Developing new therapies can be challenging, costly and time-consuming. Typically, it takes between 12 and 15 years to develop a new therapy from discovery through to launch. For approximately every 5-10 potential new therapies that start the clinical development process, only one will go on to receive regulatory approval and become an approved therapy. For Parkinson s disease and other disorders of the brain, the success rate is often lower. Conducting clinical studies is a particularly lengthy and expensive process. Due to the diversity of services required to carry out a clinical trial, and the numerous people involved, pharmaceutical companies, with few exceptions, enlist the help of Clinical Research Organisations (CROs) and the clinical unit of multiple academic institutions to help conduct these large studies. By the time phase 3 trials are reached, nearly 1 billion will already have been invested in the development of a new therapy. i The ethics of using placebo in surgical trials One of the main challenges associated with clinical trials in chronic conditions such as Parkinson s disease, in particular trials involving a surgical procedure, is the use of placebo. The use of placebo enables doctors to determine the effectiveness of a new therapy compared to not giving therapy. However, it is important to ensure that a trial participant s health is not at risk during a clinical trial. The following criteria should be adopted, depending on the individual trial and the nature of the drug involved: 7

8 1. Surgical placebo controls should be used only when no other trial design will give the information required to judge the effectiveness of a new therapy. 2. If the standard nonsurgical therapy is efficacious, i.e. capable of producing the desired or intended result, and acceptable to the patient, then it must be offered as part of the study design. The standard therapy might not be included when it is not fully efficacious, or is unacceptable to the patient (e.g. side effects, personal beliefs). 3. Surgical placebo controls should always be accompanied by an informed consent process and careful explanation of the risks, along with a description of the differences between the trial groups. The criteria listed above is just a guide and not fully representative of all trials as it can differ depending on the organisation responsible for the trial. The main risks of taking part in a surgical placebo control trial are: Participants may be required to delay or may forego receiving a beneficial therapy Physical risks such as anesthesia, bleeding, infection, and additional pain The main benefits of taking part in a surgical placebo control trial are: Contributing to advances in treating the condition affecting you personally Receiving standard medical therapy at no cost Obtaining the experimental therapy at no cost, should it prove to be effective Inclusion/exclusion criteria All trials have inclusion and exclusion criteria. These determine who is eligible to take part in a particular clinical trial. These criteria help to identify appropriate participants and ensure that, above all, the study is safe. Inclusion criteria are the key factors you must have in order to qualify for a trial. These factors usually cover age, gender, the type and stage of your disease or condition, previous therapies you have received and other medical conditions. Exclusion criteria are those factors that preclude you from taking part in a particular clinical trial. Ethical guidelines on clinical research are in place to help to protect trial participants and preserve the integrity of the science. Informed consent is an important part of the protection for anyone participating in a clinical trial. It gives you the chance to familiarise yourself with key facts about the planned study before deciding whether or not to take part. 8

9 FAQs Why are clinical trials important? A: Clinical trials lie at the heart of all medical advances. They help provide evidence on whether new therapies are safe, what side effects they have and if they are more effective than the current standard therapies. The evidence collected in clinical trials is vital in deciding which therapies work best for a particular disease or condition. Without clinical trials, a new therapy would never reach the stage where it was proved safe and effective enough to be approved for use in patients. In the case of Parkinson s disease, clinical trials may lead to the provision of new therapies that offer long-term relief of symptoms, particularly the debilitating motor symptoms of the condition such as slowness of movement, tremor and stiffness. Who can take part in a clinical trial? A: Anyone taking part in a clinical trial must fulfil the inclusion criteria for the particular study. For example, a clinical trial in Parkinson s disease may specify that a participant should have received a diagnosis of Parkinson s disease that is currently being treated with L-dopa or a dopamine agonist in order from them to be eligible. A person will be unable to participate in a trial if they meet any of the exclusion criteria for the study. Participants in clinical trials are volunteers who have given their informed consent to take part. Patients can be recruited into a trial through their doctor or hospital, or may find out about a clinical study themselves, for example by checking online listings of clinical trials that are running within a particular disease area. 9

10 What are the benefits of enrolling in a clinical trial? A: The benefits of participating in a clinical trial are: The possibility to receive treatment with a new and potentially more effective therapy to treat your condition. Greater medical care and attention than with standard therapy because close monitoring of your therapy and progress is also essential during a clinical trial. Once the trial has ended, doctors will be more familiar with your condition and in a better position to advise on the most appropriate and effective therapy. Patients participating in a clinical trial also accumulate evidence and information along the way that can help them to better manage their condition. Participating in clinical trials contributes to moving science forward, helping to find better therapies for the future. The medications that you take now are available only because people before you have volunteered in clinical trials. What are the risks of enrolling in a clinical trial? 10 A: The risks of participating in a clinical trial are: There may be undesirable side effects to the therapy. A healthcare professional will explain the possible risks and side effects during the informed consent process. The therapy may not be effective for the participant. The study might have time and travel requirements that are demanding. Enrolment on a clinical trial may mean that you are unable to participate in other clinical trials in the future.

11 In order to participate in a clinical trial you must be completely committed to the trial. Participating in a clinical trial may affect the relationship with your caregiver, so should be considered before enrolling. Patients participating in a clinical trial should also keep in mind that they may not receive the experimental therapy because they may be randomly assigned to receive either a different dose of an existing therapy that is considered standard therapy for the condition, or a placebo (dummy drug). In many studies, the researcher is not aware of who is taking the experimental therapy and who is not. How can I find out more about clinical trials in Parkinson disease? A: Speak to your doctor to find out more about on-going clinical trials in Parkinson s disease or visit the following websites: PDtrials: - Clinical Research Network - FoxTrial Finder - European Parkinson s Disease Association (EPDA) - Cure Parkinson s Trust - Parkinson s UK - For a complete, searchable listing of all current clinical trials, including those that are actively recruiting patients, go to i ABPI. Celebrating International Clinical Trials Day. Medicine Development Process Infographic. Available at Last accessed June

12 Co-funded by the Seventh Framework Programme of the European Union Date of preparation: June 2013