• Disease-modifying therapies (DMTs) for multiple sclerosis (MS) must be proved effective in a series of clinical studies before achieving U.S. Food and Drug Administration (FDA) approval.
• By the time a DMT is approved, it has been studied for many years in hundreds or thousands of people with MS and has been shown to be significantly more effective than existing treatments.
• The vast majority of new drugs studied never reach review by the FDA.

Disease-modifying therapies are medications approved by the FDA to treat multiple sclerosis. DMTs modify the immune system to reduce MS flares and slow disease progression. More than a dozen DMTs are approved to treat different forms of this demyelinating condition.

Many people living with MS wonder how the effectiveness of DMTs is determined and how to know which option will work best for them. DMTs work differently for individuals, and it’s up to you and your neurologist to determine which drug will help you meet your treatment goals.

Becoming more familiar with the FDA approval process for DMTs may help you understand effectiveness. Only medications that are deemed safe and effective for MS are approved to become available as treatment options.

Phases of Clinical Studies

The FDA approval process requires medications to go through three phases of clinical trials, which are research studies that test drugs’ efficacy and safety. In some cases, DMTs have been studied for almost 20 years before reaching approval.

Experimental drugs first go through phase 1 and 2 clinical trials. These studies are designed to make sure that the drug is safe and common side effects are generally tolerable, as well as to find out if there are any rare but severe side effects. Investigators also use these early studies to determine the best dose and monitor for common side effects.

Phase 3 Studies

If a drug makes it past these phases, it will then go into phase 3 studies involving hundreds or thousands of people with MS. The main goal of these studies is to compare the investigational drug with currently available therapies. (Placebos — sham medications or “sugar pills” — are used in MS clinical trials only in very specific situations and always with the informed consent of all participants.)

Phase 3 trials are also used to determine how effective the drug is in a larger population of people and see if any adverse reactions to the drug occur. Phase 3 studies can last one to four years, long enough to reveal rare or long-term side effects.

Alternative Approval Process

In some cases, DMTs have gone through the FDA’s “alternative” approval processes. These systems accelerate a promising drug’s path to approval to address unmet treatment needs in specific populations or forms of MS. For example, one DMT was designated as a breakthrough therapy for treating relapsing-remitting MS (RRMS) in children and adolescents older than 10 years because study results showed the drug was more effective than available therapies.

Determining Endpoints and Goals in DMT Studies

In all clinical studies of MS medications, investigators look at endpoints, or their goals for the medication. Rules and standards of the study are in place before research begins to make sure results will show whether these goals have been met. Investigators also select tests for how they measure the participants’ progress or improvement.

Clinical trials for DMTs use outcome measures including:

• Disease progression visualized with MRI scans for lesions
• Worsening of disability
• Relapse rate (number of relapses in a given period)

In many MS clinical trials, participants will have an MRI scan and disability testing to set a baseline before the study starts. Phase 3 clinical trials often use the Expanded Disability Status Scale (EDSS) to measure and track disability progression. MRI scans are used to reveal brain lesions before and after treatment to determine any change in the central nervous system while taking the drugs.

Once the baselines are established, participants are typically divided into two groups. In MS clinical trials, the control group usually receives a DMT already approved for treating MS. The other group receives the investigative drug. The goal of the study is to determine whether the new drug is more effective at achieving the goals compared with the control DMT.

Analyzing Results

At certain times throughout the study, the participants undergo follow-up MRI scans and disability testing to measure disease activity. The data is analyzed and used to compare how effective the investigative drug is compared with controls.

Is the New Treatment Significantly Better?

Statistical analyses of the collected data determine if the study results are significant. Statistical significance can be a difficult concept to understand, but it can be explained by either accepting or rejecting the null hypothesis. The null hypothesis assumes that there is no difference between the investigational DMT and current therapies. The investigators can then run statistical tests to determine if the null hypothesis is true (accepted) or false (rejected). If the data does show statistical significance — that the investigational drug is more effective than other treatments — then the null hypothesis is rejected.

DMTs are also categorized by their relative effectiveness, with some considered highly effective. However, highly effective DMTs may be more likely to carry the risk of rare but serious side effects.

What Are the Side Effects?

To determine the drug’s safety profile, the investigators also take note of any side effects, adverse reactions, and complications that participants experienced during the trial. If the DMT is eventually approved, these side effects will be listed on its official label.

If any rare but severe adverse effects were revealed in the study, the DMT (if approved) may receive a boxed warning, also referred to as a black box warning. This is the FDA’s strongest warning, designed to let consumers know about potential serious side effects.

FDA Approval

When the new drug application is submitted to the FDA, the agency forms a review team to go over the data submitted. This team includes medical doctors, pharmacologists, microbiologists, chemists, and other experts in neurology or other fields who are tasked with going over all the evidence about the investigational drug. Each reviewer writes a summary of their conclusions and recommendations for the new drug application. In the end, the reviewers must believe that the drug’s benefits outweigh the risks of the side effects.

FDA inspectors will also travel to the clinical trial locations to look for any evidence of data tampering, which could affect study results. After all the data is collected and reviewed, a senior official at the FDA will determine if the drug is approved.

What If a Drug Is Not Approved?

In some cases, a drug application is not approved by the FDA review team. Perhaps there are problems with the submitted application, or weaknesses in the clinical trials give the reviewers reason to doubt the results. They may also deny an investigational drug approval if the data shows the drug is not more effective than currently available therapies, is not tolerated well by participants, or has dangerous side effects.

The majority of investigational drugs never make it to this stage. Many drugs are rejected after each clinical trial phase and don’t advance to the next step. For example, for every 100 investigational drugs that go into phase 1 trials, only 70 make it to phase 2 trials, and just 33 of 100 advance to phase 3.

Choosing the Right DMT

All currently available DMTs went through rigorous testing, sometimes for decades, before hitting the market. These medications are safe and effective for many people with relapsing MS, but each comes with potential side effects.

As one MyMSTeam member put it, “Meds and side effects are individually based. I’m on my fifth MS med, and I’m still waiting to see if it’s effective. Unfortunately, you may have to try several.”

Figuring out which disease-modifying treatment to use is subjective, so it’s best to consult with your health care team. If you are wondering whether it’s time to switch your MS treatment, they can help you make the best decision for your MS care and quality of life.

Talk With Others Who Understand

MyMSTeam is the social network for people with multiple sclerosis and their loved ones. On MyMSTeam, more than 187,000 members come together to ask questions, give advice, and share their stories with others who understand life with MS.

Do you still have questions about how DMTs reach approval by the FDA? Have you ever participated in a research study? Share your questions and experiences in the comments below, or start a conversation in Activities.