9/29/2005
ALS and Clinical TrialsWhat are Clinical Trials?
Clinical trials carry out tests on people to see whether a candidate therapy is safe and works to counter the effects of a disease.
Before human patients are the subjects, therapy is tested in cells or tissue grown in the lab, and then in animals, to provide the best possible assurance that a drug will be safe for people to take.
How Do Clinical Trials Proceed?
A pilot trial is a very first look at a candidate therapeutic in people, a study that may be observational with too few patients to allow a formal statistical analysis. Pilot testing must be able to inform further testing of a candidate therapy. A pilot study paves the way for subsequent full scale clinical trials. Therefore, a pilot trial should establish the number of participants needed for a formal clinical trial and criteria to include or exclude certain people. This will protect participants and provide the best judgment of safety and effectiveness.
Clinical testing Is Divided into Four Phases:
Phase I testing looks at the safety of a candidate treatment, often in just a few people. Participants are examined for any adverse reactions or side effects. If any appear that are judged to be too dangerous, testing is halted and the drug will not advance any further in the clinical trials process.
A Phase I trial enrolls perhaps ten or twenty subjects. For candidate therapeutics in many diseases, this stage of testing can be in healthy volunteers. But in ALS, the lack of effective treatment makes it likely that any new candidate is tested in patients.
In ALS, a therapeutic will need to enter the nervous system. Also, ALS compromises the ability to maintain nutrition and adequate tissue oxygenation as breathing and swallowing weaken. Any new ALS therapeutic must be shown safe even in the context of altered nutritional status and oxygenation common in ALS. Thus, even initial testing must determine safety in patients who have the disease, when it comes to new therapies for ALS.
Phase II testing attempts to determine the optimal dose, route (by mouth, by injection) and timing of doses of the candidate treatment. Information about a drug’s ability to help in the disease may be obtained in the course of Phase II testing, but such findings are not able to reliably predict a candidate’s effect. Usually less than a hundred patients are involved.
The therapeutic effect of the candidate is specifically sought in Phase III testing, once Phase I and II trials show safety and yield the optimal dose. This is the stage of testing that enrolls enough patients to allow a statistical judgment that a treatment is effective. Phase III trials usually require hundreds to thousands of participants.
Phase IV testing is for drugs already approved for sale to treat a specific disease or diseases (termed a treatment’s indications). This stage of clinical trial allows further gathering of data on large groups of people who are taking the treatment for a prolonged period of time. Often a rare adverse effect only becomes evident after a drug is marketed simply because there has been enough exposure to the drug to reveal the rare occurrence.
Who Can Participate in a Clinical Trial?
There may be limits on who can volunteer to be part of a clinical trial. The design of a trial ensures that the most reliable measures possible are collected to best judge a treatment’s effects.
Due to requirements for producing reliable data, patients may have to be of a certain age, gender, stage of disease, or even race, to participate for many clinical trials. Studies must address any anticipated risk of a drug for patients of a certain age, gender, race, or physical condition, or interaction with other drugs being taken and protect participants from being exposed to undue risk.
For ALS, restrictions are often looser to participate in clinical trials than for other conditions that are not so devastating or rapidly fatal. Nevertheless, ALS patients in clinical trials are required to fulfill certain criteria of the disease or disease severity (“Inclusion criteria”) and might be ineligible if they show certain other characteristics (“Exclusion criteria”).
How are Clinical Trials Designed?
Phase II and Phase III trials are usually randomized, placebo controlled, double blind studies that include a statistical analysis.
Statistics:Clinical trials can only test relatively few patients and must make predictions from a few people that will most likely hold for the patient population as a whole. Statistics provide the means to judge if a change induced by drug treatment is likely to be a real, reproducible change, and that what doctors see in a restricted set of patients is likely to hold true for the entire population of patients with that disease.
So the patients must be as clearly characterized and represent the disease picture as closely as possible. That allows researchers to take data from clinical trials and predict that the entire population of patients will show the same results if given the same treatment.
Placebo:The placebo effect is well known in medicine as a temporary improvement in pain or other symptoms of a disease that follows a fake pill. It is a real effect. But it is not due to the active properties of a drug. So testing of any new treatment must insure that the effect is due to the drug and not to the power of positive thinking or to the extra attention from the medical staff that comes with participation in a clinical trial.
Patients in clinical trials have more doctor visits and tests than those who are not in trials. This also must be taken into account, and placebo treatment with blinding (see below) does so.
For diseases such as cancer, where effective treatments exist, new drugs can be tested against the standard of care. But in ALS, with only one approved drug that does not have a strong effect to prolong life or slow progression, many argue that candidate therapies should still be compared to a placebo.
Blinding:
Clinical trials often are double blinded, meaning neither the clinicians nor the patient knows which drug is taken: placebo (or standard treatment) or candidate treatment. Unconscious bias can creep in when an investigator looks at data knowing which treatment generated the numbers or records symptoms from patients on the test drug. And patients can give more attention to perceived changes if they think active drug may have created them. In a blinded clinical trial, only a central office knows the treatment assignment until the study ends but can unblind a patient or the entire study if needed.
Randomization:
Often trials will assign patients to two or three treatment groups at random. This prevents any bias from influencing what patient gets which treatment. As patients enroll in a trial that is randomized, they are assigned by computer (kind of like drawing numbers from a hat) to a treatment group.
It is better to pick from a hat than to inadvertently pick those people with a milder form of the disease or a slower course of progression to receive the test drug. When a study is analyzed and the results presented, the researchers are always careful to consider if the groups of patients were indeed well randomized as to characteristics such as age, gender, stage of disease, and so forth.
Control:Control refers to a control group intended for comparison to the group of patients receiving the candidate treatment. The control group is the patients who are taking a placebo or the standard of care treatment. If a control group is not included, researchers would be less certain that the patients taking the candidate therapy were not getting better by chance fluctuations in their illness, as opposed to a direct effect of the drug.
Fluctuations in disease progression are documented for many illnesses including ALS. Simple hope that a new treatment will work can color expectations and perceptions. A patient’s speech can appear clearer. A patient can gather strength to sit up unassisted or take a few steps unaided. Decline in abilities can slow or plateau. These are real effects of positive thinking. A control group helps to balance effects of the mind against effects of a drug.
What are Outcome Measures?
These are the measurements that are defined at the outset of a trial as the sought for action of the drug candidate. For ALS, survival time is an example of an outcome measure that an effective treatment should change. Other outcome measures that are useful in ALS are tests of muscle strength or measures of breathing. Quality of life, measured by self report or caregiver report, is a desirable measure to include in ALS clinical trials. Rating scales are available that rate various aspects of life with ALS including ability to move and to carry out activities of daily living, as well as problems with breathing and eating. An example is the ALS functional rating scale (ALS-FRS).
What are Surrogate Markers?
Some disorders have known signs that imply the disease process is interrupted. These measures can serve as a surrogate for the actual desired outcome. In heart disease, lowering blood pressure or cholesterol would be valid surrogate markers as these changes are accepted to lower the risk of heart attack and death. In ALS, surrogate markers are as yet unproven but are suggested. For instance, breathing capacity appears to predict survival. Improved and accelerated clinical testing in ALS will surely follow once good surrogate markers of disease progress are identified.
Where are Clinical Trials Carried Out?
Many clinical trials are at medical centers of teaching hospitals linked to a medical school. But private practice physicians can also be part of a clinical trial and be able to enroll his or her patients.
Different organizations may sponsor a clinical trial. These can include federal agencies, private charitable organizations such as The ALS Association, or drug or biotech companies.
What is an IRB?
An Institutional Review Board (IRB) is required to safeguard patients participating in clinical trials. This is a committee of experts convened by an institution to review biomedical research involving humans as subjects. An IRB will approve the initiation of the research and then reviews its progress to ensure the safety of the participants. The board includes health professionals, clergy, and members of the public. Every institution that oversees clinical testing must have an IRB.
The IRB meets regularly to follow the progress of a trial. It can call a halt to a trial if unanticipated risks appear, or if a treatment is showing such clear evidence of beneficial effect that it would be unethical to not make it widely available.
In addition to the IRB, clinical trials in the Phase I - III category have a Data and Safety Monitoring Board (DSMB) of scientists, statisticians, and other experts that watches for adverse effects. It ensures that the data collected are as complete as possible and can halt a trial if risks appear, or if the objectives of a trial are met.
What is a Protocol?
Each clinical trial has a detailed description of how the trial will be carried out, what parameter is being tested, and what measurements will be taken at what times. Details of patient characteristics are also stated beforehand (eligibility criteria). Each center or physician enrolling patients follows the same study protocol. The first step to initiate a trial is having the IRB approve the protocol.
What is Informed Consent?
Clinical trials are entirely voluntary and patients can withdraw at any point. Participants in clinical trials learn of and must read and sign a statement listing clearly the risks and benefits of taking an experimental drug.
Informed consent is a process and not a piece of paper. It must continue throughout a clinical trial. Patients have the right to understand what is happening throughout the trial, if risks and benefits change.
Risks and Benefits to Participating in Clinical Trials
Setting eligibility criteria defines the characteristics of the patient who can most safely participate in a clinical trial. For instance, if a candidate drug is known to be broken down by the liver, patients will be tested for their liver function, which must be adequate to participate. Otherwise, potentially dangerous levels of drug might accumulate in the bloodstream if the liver cannot detoxify properly.
Risks to patients include effects of the candidate treatment that are yet unknown, for instance, if the drug indeed affects liver metabolism and this only becomes evident during testing. This kind of potential problem is why drugs are tested extensively in animals before use in people. But sometimes interactions with particular patients are not revealed until clinical trial.
By contrast, approved drugs have been taken by many patients for years, so risks are usually known.
Other risks to patients participating in clinical trials include increased cost as well as increased risk. Health insurance does not usually cover experimental treatment.
Another adverse aspect to clinical trials is participants may have to give more frequent blood samples and keep a detailed record of symptoms than if receiving usual care for their illness.
Benefits include the chance that a new drug is more successful at treating the participant’s disease than existing treatments. Also, as mentioned, clinical trials involve more frequent doctor visits and more frequent testing which can help patients. Patients in clinical trials who do not receive the candidate treatment do receive the best standard of care for their disease.
A benefit to participating in a clinical trial is that the questions answered can benefit all patients with the disease. Even if a candidate treatment fails to hold promise, the results of any clinical trial give new insight and direction to those working to solve the disorder.
What is the role of the FDA?
The Federal Food, Drug, and Cosmetic Act of 1938 set up the Food and Drug Administration to ensure that any new drug to be sold is safe and effective. The FDA staff reviews preclinical results that the testing parties are required to submit to demonstrate that a new drug can be tested safely in people (see IND below). If testing shows that a drug is safe and effective, the FDA must approve the drug for sale and state what information is to be provided with the drug to physicians and patients (in the package insert) so it can be used properly.
The FDA also inspects IRBs to help protect the rights and safety of human research subjects.
What is an IND?
An Investigational New Drug Application must be submitted to the FDA before testing begins of a new drug in people. The IND application consists of the plans for the study and details of the composition of the drug, how it is manufactured, and results of tests in animals.
What is Compassionate Use?
The FDA allows people to be treated with promising drugs still in clinical testing, provided an illness is life threatening and has no other effective treatment. These “expanded access protocols” are allowed while clinical researchers are still in the process of formal clinical trials that are supplying information that the drug is safe and likely to be effective. Programs for expanded access to experimental drugs include the treatment IND for people for whom there are no other treatment options.
The FDA also designates drugs for priority review that supply a real advance in treatment, as opposed to drugs that merely make available another option to ones already on the market. The agency will mobilize personnel and resources to plan for a streamlined review when a priority drug is first put into clinical testing. The special “accelerated approval” process is also available with expedited FDA review for new treatments for otherwise life threatening illnesses.
Who Pays for Patient Costs in Clinical Trials?
This will vary according to the clinical trial and a patient’s insurance. Be sure to ask this very important question when considering whether to participate.
Current Clinical Trials for ALS
Resources:
http://www.rtanswers.org/treatment/clinical_trials.htm
http://www.clinicaltrials.gov/ct/info/whatis - whatis
http://www.cancer.gov/clinicaltrials/understanding/what-is-a-clinical-trial
http://cis.nci.nih.gov/fact/2_11.htm
http://www.wfnals.org/guidelines/1998airlieclintrial/airlie1998guidelines.htm
http://www.clinicaltrials.gov/ct/info/links
http://www.fda.gov/cder/about/whatwedo/testtube-3.pdf
http://www.fda.gov/fdac/special/newdrug/speeding.html
http://www.fda.gov/cder/about/whatwedo/testtube-5.pdf
