As we learn more about multiple sclerosis (MS), researchers continue to look for new treatment options. Disease-modifying therapies (DMTs) are medications proven to help slow disease progression in MS and reduce the number of flares (relapses). On average, developing one new medication takes 10 to 15 years.
Before the U.S. Food and Drug Administration (FDA) will approve a new DMT for public use, the drug first goes through a series of studies known as clinical trials. Investigators — doctors and researchers who run clinical trials — must be able to prove through these trials that a new medication is safe and effective when compared to already-approved therapies.
The FDA’s approval process is designed to ensure that for all drugs that reach the market, the potential benefits of taking them outweigh the potential risks, such as side effects.
Before a new drug can be given to humans, investigators first have to show that it’s safe in preclinical studies. These small preclinical studies use lab-grown cells or animals to determine the toxicity of a drug and what a safe dose may be.
Once all preclinical data is collected, the investigators from a pharmaceutical company or research institution submit an investigational new drug (IND) application to the FDA. The FDA reviews the IND application to determine whether the drug can be used in clinical trials.
Once the FDA determines the drug is safe to test on humans, investigators can begin clinical trials. There are three phases of clinical trials used to look at different aspects of a medication, including dosing, side effects, and efficacy (whether it produces the intended result).
In early clinical trial phases, investigators are interested in learning about the drug’s safety and any potential side effects. Although preclinical studies can help give a good idea of dosing, investigators won’t know exactly how a drug works until it’s given to humans.
Traditionally, phase 1 studies consist of 20 to 100 healthy volunteers. During a phase 1 study, participants are given the DMT being test at different doses to find which dose works best while remaining safe. Investigators try to find a balance between giving enough of a drug for it to be effective while balancing the unwanted side effects that may accompany a higher dose. According to the FDA, only 70 percent of drugs move into phase 2 clinical trials.
In phase 2 clinical trials, investigators expand on the results from phase 1. These studies have several hundred volunteers with MS who try the medication dose determined from the previous phase. Depending on the form or forms of MS being targeted in the trial, researchers may select volunteers with primary progressive MS (PPMS) or relapsing forms of MS — relapsing-remitting MS (RRMS), clinically isolated syndrome (CIS), and active secondary progressive MS (SPMS).
Because these studies have more volunteers, they help investigators find less common side effects that may not have been seen in phase 1. Only 33 percent of drugs that reach this stage move to phase 3 clinical trials.
The final and largest of the clinical trial phases is phase 3, which is used to determine whether a drug is effective in treating a disease or condition. These studies recruit hundreds to thousands of volunteers to take either a new drug or a currently available therapy for comparison. Phase 3 studies also give investigators even more information about a drug’s safety and the side effects that participants experience.
In MS clinical trials, placebos — “fake” sugar pills or sham medications — are used only in very specific situations, and volunteers are informed they may receive a placebo. Instead, the standard in MS studies is to give the control group a currently available FDA-approved DMT to compare results with the new medication.
New DMTs are required to meet certain outcomes or treatment goals that measure how effective they are. These outcomes are set before a clinical trial begins to ensure the study goals and standards are the same throughout the trial.
Unlike other medications used to manage MS symptoms, DMTs are prescribed to help slow disease progression. With this, outcomes in DMT clinical trials don’t measure symptom improvement. Instead, they measure disease progression, disability progression, and relapse rates.
MS is a progressive disease. Over time, damage to the central nervous system (CNS) and symptoms get worse. Disease progression in MS is measured by the formation of new lesions or the worsening of lesions a person already has on their brain, retina, and/or spinal cord.
Doctors use MRI scans to visualize these lesions. At the beginning of a DMT clinical trial, participants have MRI scans taken to establish a baseline (information found at the beginning of a study) to compare to later. Throughout the study, they’ll continue to have scans to monitor any changes. The goal of new DMT medications is to slow disease progression and changes in lesions over time.
Disability in MS is typically measured using the Expanded Disability Status Scale (EDSS). This scale uses numbers 1 through 10 to quantify disability as a combination of muscle, speech, vision, and memory problems.
At the beginning of a DMT clinical trial, participants have their EDSS score taken to establish a baseline. At the three- and six-month points of the study, a neurologist will measure their EDSS score again to see if and how much their MS has progressed. The goal of new DMT medications is to slow disability progression more than currently approved therapies.
MS is a disease with periods of flares and remissions when MS symptoms worsen and improve. In DMT clinical trials, investigators track how often participants experience relapses as a way to measure disease activity and progression. Remission is the period after a relapse when MS symptoms either partially or fully disappear.
The annualized relapse rate calculates the average number of MS relapses a group of participants has during one year. The goal of new DMTs is to reduce this number compared to currently available therapies.
Once investigators have completed their trials, they compile all data from preclinical and clinical studies to submit a new drug application (NDA) for FDA approval. A team of doctors, scientists, and other neurology experts at the FDA review the NDA to determine whether a new DMT is safe and effective.
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The review team considers the results of the clinical trials, particularly in how effective the new DMT is compared to currently available therapies. They also carefully consider the outcomes and the participants’ experiences to weigh the risks and benefits of the new medication.
At this stage, the FDA may still deny a new medication if it doesn’t slow disease progression as well as other treatments, if participants couldn’t tolerate it, or if it has dangerous side effects. Once all data has been reviewed — if the application is successful — a senior FDA official makes the final decision to approve the new DMT.
After a drug has been FDA-approved, the FDA can request a phase 4 study (postmarketing study) to look at side effects that might have been missed in phase 1, 2, and 3 trials.
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