The Long Road to Drug Approval

Finding a treatment or cure for any given illness is no easy task. Drugs or other agents considered for treatment are usually identified or developed through exhaustive laboratory experiments and computer models of a disease. While research in the lab can show promising results and be very exciting, this doesn't necessarily mean that the treatment will be a success. Additionally, the US Food and Drug Administration (FDA) requires years of testing and extensive analysis before any new medication actually becomes available to the public.

For individuals seeking a cure for a particular ailment, this long process can be frustrating; and for some, it may even appear unjust. But experience has shown that without these mandated trials and stringent rules and regulations, consumers would be vulnerable to unproven treatments with potentially dangerous or even fatal adverse effects.

The Preclinical Phase
The road for any new drug begins with the preclinical phase, where the agent is administered to animals and tested for safety. To assist with the research of drugs being considered in the treatment of MS, experimental models of MS have been developed. These include experimental allergic encephalomyelitis (EAE) and Theiler's murine encephalomyelitis virus (TMEV). Once the lab animals have been infected with one of these diseases, prospective MS treatments may be used on these animals to determine if the drug has any effect on the animals' condition. If disease activity in the animal version of MS is slowed or stopped by one of these experimental drugs, this gives researchers the hope that the drug may work similarly in people with MS.

Phase I
The next step for a drug being investigated is to enter a phase I clinical trial. At this phase, FDA approval to conduct the trial has been obtained. The purpose of a phase I trial is to test for safety in humans. Typically, less than 100 unaffected, healthy, and young
volunteers take part in such a study -- frequently college students -- who are often paid to participate.

While conducting a phase I trial, investigators may observe how the human body responds to the medication (how the drug is absorbed, metabolized, and excreted). The investigators will also determine safe doses and related side effects. Phase I trials are referred to as "open label" and "unblinded," because everyone (patient, medical staff, and investigators) knows the drug and dose that each person is receiving. In later trials, patients and sometimes the medical staff will not be aware of who is receiving the real drug and who is receiving a placebo (a medication that looks the same as the drug being tested, but has no active ingredients or physical value of any kind). Trials using placebos are referred to as "blinded."

Phase I trials can take several months to one year to complete. Sometimes a few individuals who have the disorder (such as MS) will be given the drug to study its effects before going on to the next phase. Approximately 30 percent of the experimental drugs being studied do not continue beyond phase I testing.

Phase II
The other 70 percent go on to phase II studies, which typically last from several months to two years. The safety of these drugs has been established, as well as side effects and recommended doses. In this phase, between 100 to 300 people with the condition (such as MS) are given either the active drug or a placebo, to determine the drug's effectiveness and to continue to study its safety.
Individuals participating must qualify according to the study's eligibility criteria (which specifies certain age, gender, disease type, medical history, and other limitations). These factors are all included in the study's protocol, which is a written study plan that states the purpose of the trial, how long the trial will be conducted, the steps involved, who may participate, the treatment each participant will receive, and how the data will be collected and analyzed.


Phase II studies are often "double blinded." This means that neither the participants nor the medical staff administering or evaluating the new treatment are told who is receiving the drug and who is receiving the placebo. Results are reported to members of a separate medical staff, who are aware of what each patient is receiving. Studies that are double-blinded are considered more "rigorous," i.e., scientific, or likely to be correct.

Studies involving a placebo are said to be "placebo-controlled," meaning that a portion of the participants will receive the active drug, and the other portion receives a placebo. This is necessary because of the "placebo effect," which is a physical or emotional change that occurs after a substance has been given -- but is not the result of any special property of the substance. In other words, study participants often experience a short-term improvement in their condition at the onset of the study -- even if they are in the placebo group. The reason for this phenomenon is not totally known, but it occurs particularly often with those in MS trials. Those in the placebo group are referred to as the "controls."

These studies are also "randomized." Based on chance, randomization is a method that assigns participants to a treatment group (such as active drug vs. placebo or high-dose vs. low-dose). It minimizes the number of differences between the groups by equally distributing people with certain characteristics to the different treatment groups.

Specific Challenges with MS Trials
Trials for new agents in the treatment of MS pose particular challenges to researchers. Perhaps the greatest obstacle faced is the behavior of the disease, which naturally relapses and remits at the onset for 80 percent of the people who have MS. When a new agent is administered, clinicians have difficulty determining if an improvement or worsening was caused by the particular treatment, if it occurred independent of the treatment, or if the treatment enhanced or lessened the positive or negative outcome.

For this reason, matched controls are needed in an effort to determine what the outcome would have been without treatment. Controls must be carefully selected, with particular attention given to demographic characteristics (such as age, gender, and duration as well as severity of MS) prior to enrollment.

Trials for MS are also difficult to design and evaluate since the cause of this disorder is still unknown and the mechanisms involved with its development are extremely complex. Additionally, MS trials are often small (fewer than 150 patients), short in duration (less than three years), and outcome measures (such as exacerbation rate and severity, change in disability, and disease progression) are difficult to consistently measure.

While these difficulties may challenge the investigators, they certainly do not prevent the researchers from recognizing a successful treatment -- as proven by the approval of the five long-term MS treatments now available (Avonex(r), Betaseron(r), Rebif(r), Copaxone(r), and Novantrone(r)). And as these trials for MS medications continue to increase, the protocol will continue to reflect and improve upon the study design that is necessary to accurately evaluate a drug's effectiveness for the treatment of MS.

Phase III
Of all the drugs that start out in preclinical studies, only about one-third reach the important phase III level. These are large, multicenter trials, with an estimated 1,000 to 3,000 participants receiving treatment and evaluation at several different trial
locations. Phase III trials can take several years to complete, and are usually randomized, placebo-controlled, and double-blinded. Clinical trials at this level reveal further details about a drug's safety and efficacy, while providing more insight into any additional benefits, side effects, and adverse reactions.

More than two-thirds of the drugs that enter phase III studies successfully finish this phase. After phase III, a data analysis is done to determine the overall effectiveness and safety of the drug or therapy.

Drug Approval
If the results are favorable, an application for approval of the drug is submitted to the FDA, whose panel reviews the results and recommends approval if it finds the treatment to be beneficial and safe. Once approved, the drug company conducting
the research may then prepare to market its drug in the US for the specific indication (or illness) for which it was approved.
Physicians may have the option to prescribe an approved medication for other indications if appropriate. Should such a drug return to clinical trials for another indication, early trial phases for safety may not need to be repeated.

Phase IV
Phase IV trials are conducted after a drug has been approved. Participants are enrolled to further monitor safety and side effects, while evaluating long-term efficacy. Pharmaceutical companies also use these studies to compare the new drug's long-term performance and cost-effectiveness with competitive drugs and other treatment options. They also look at how the patients' long-term quality of life is affected. Phase IV trials are not placebo-controlled or blinded, and everyone enrolled has previously or is presently taking the active drug.

Non-FDA Trials
As a side note, the FDA is not involved in all clinical trials. Adam Roberts, director for MSAA's Mid-South Region points out, "The FDA does not control all of the clinical trials being carried out in America today. Trials on therapeutic equipment or procedures usually fall outside their domain. The largest increase in non-FDA trials is those for herbal remedies and food supplements. Most of these trials are carried out in accordance with FDA guidelines and provide excellent scientific data. The MSAA-sponsored trial in cooling is an example of a valid alternative trial. There are, however, some trials carried out purely to substantiate a manufacturer's claim through careful selection of participants and manipulation of the data."

Trial Funding and Location
Drug trials are normally funded by health organizations (such as the different MS agencies), pharmaceutical companies (that hope to eventually market the drugs being tested), research institutions (such as medical universities), and federal agencies (including the National Institutes of Health [NIH] and the Department of Veterans Affairs [VA]). Clinical trials are conducted at various medical sites -- including hospitals, clinics, and doctors' offices. A clinical team of healthcare professionals, including doctors, nurses, social workers, and others, oversees the trials and provides individualized attention to the participants.

Participating in a Trial
According to the CenterWatch Clinical Trials Listing Service(tm), "Every year, several million people participate in clinical trials to support new drug applications that are submitted to the FDA... As more and more drugs enter research and development, more people are needed to volunteer for clinical trials so that these drugs can be studied and ultimately introduced into the market."
Participating in clinical trials does present risks, and the fact that millions of people risk their own health each year for the
benefit of others is remarkable. Despite the risks involved, individuals participate in clinical trials for a number of reasons.
According to the NIH, participants in clinical trials gain the following benefits and take the following risks:

Benefits
Clinical trials that are well-designed and well-executed are the best treatment approach for eligible participants to:

Risks
The risks to clinical trials include:

Qualifying for a Trial, Informed Consent, and Patient Rights
As mentioned earlier, a prospective clinical trial participant must meet the different eligibility requirements as stated in the original study protocol. These include age, gender, type and stage of disease, previous treatment history, and other medical conditions. If an individual qualifies for a trial, he or she will be checked and monitored by a team of healthcare professionals throughout the trial, and will be contacted even after the study has been completed.

During the trial a participant may be required to have far more tests and office visits than one would normally have with a specific condition. Frequent contact with the research staff is essential and the participant's travel and other expenses may be reimbursed -- but this is something that would be explained prior to beginning a trial.

Prior to committing to participate in a trial, an individual is given "informed consent." This is a full explanation of all the important facts about the trial, and it also continues to provide information to participants throughout the study. The research team will provide an informed consent form which includes all the trial details, such as the risks and potential benefits, the purpose of the trial, when it will begin and end, required procedures, and who to contact if the participant has questions or should any problems arise. If English is a second language for the participant, a translated version will be provided.

Anyone wishing to participate must sign the informed consent form, although this is not a contract -- and a participant may leave the trial at any time. Should an individual decide to do so, he or she should always let the research team know the reasons for leaving the study.

The NIH states that a participant's safety is protected by federally regulated, built-in safeguards. The researchers must follow a carefully controlled protocol, and as the trial progresses, report trial results at scientific meetings, to medical journals, and to government agencies. Participants' names remain secret and are not mentioned in the reports. Additionally, an Institutional Review Board (IRB) approves all clinical trials and periodically reviews the research. This is a committee of physicians, statisticians, researchers, community advocates, and others to ensure that a clinical trial is ethical and that the rights of study participants are protected.

How to Prepare and What to Ask
According to the NIH, a potential participant should prepare for his or her first meeting with the study's research coordinator or doctor by:

Additionally, anyone considering participation in a trial should know all the details of the study, much of which is found in the informed consent. While most of the following questions may already be answered, a study candidate should review these questions (as suggested by the NIH) and discuss any unanswered questions with the health care team. These questions are:

For More Information
More drugs to treat MS are being tested than ever before. This means that the MS investigators and pharmaceutical companies have a need for clinical trial participants to help investigate new, potential MS medications.

If you are interested in getting more information about clinical trials, finding out about trials that are presently planned or being conducted, or if you would like to participate in a trial, several resources are available to you. The following organizations have much to offer in terms of clinical trial information:

National Institutes of Health (NIH)
www.clinicaltrials.gov
Brain Resources and Information Network:
(800) 352-9424

Food and Drug Administration (FDA)
www.fda.gov
Center for Drug Evaluation and Research:
(301) 827-4573

National Multiple Sclerosis Society
www.nmss.org
(800) 344-4867
Consortium of Multiple Sclerosis Centers (CMSC)
www.mscare.org
www.narcoms.org
CMSC/NARCOMS patient registry:
(800) 253-7884

CenterWatch
www.centerwatch.com

Community Outreach Network
www.clinicaltrials.com
(800) 664-5099

Sources for this article include: