What are follow-on disease modifying therapies (FO-DMTs)?
Follow-on disease modifying therapies (FO-DMTs) include generic drugs, complex generics, and biosimilars. Generics are “copies” of reference (brand-name) DMTs, expected to have the same pharmacologically active ingredient, dosage, route of administration, pharmacologic characteristics, efficacy, safety, and intended use. Complex generics are generic drugs which are pharmacologically more complex from standpoint of active ingredients, formulations, or routes of delivery. Biosimilars are generic versions of biologic drugs (active ingredient is produced or extracted from a biologic source).
What is the rationale for FO-DMTs use?
DMTs represent a major portion (>50%) of direct medical costs in multiple sclerosis (MS) care. Despite a wide range of available DMTs for MS, medication costs have remained high. FO-DMTs are a potential way to lower the cost and therefore enable wider access to MS DMTs, without compromising efficacy or safety.
How are FO-DMTs approved and regulated?
The approval process and regulation of FO-DMTs is different from that of new drugs. Different areas or jurisdictions have different rules. However, processes are rather similar in the United States (US), Canada, and Western Europe, where standards set by Food and Drug Administration (FDA), Health Canda, and European Medicines Agency (EMA) are followed, respectively. Steps set by these organizations ensure that FO-DMTs demonstrate an acceptable pharmacological profile, which should support equivalent safety and efficacy as the reference DMTs. In the US, generics must demonstrate equivalent pharmaceutical characteristics (active ingredient, dosage, purity, route of administration) and pharmacokinetics to the reference drug, which typically requires at least one human pharmacokinetic/pharmacodynamic trial. Therapeutic equivalence (safety and efficacy) is inferred from the reference drug. Although biosimilars also need to be highly similar to the reference biologic product, minor differences in clinically inactive components may affect their properties, notably immunogenicity. Therefore, biosimilars usually require at least one human study to assess pharmacokinetics, pharmacodynamics, and clinical performance (safety, efficacy, and immunogenicity).
Approved generics are eligible for interchangeable use with the reference medication. State laws across US vary and direct prescriber input may be needed before a switch is allowed at the pharmacy level. Biosimilars must meet additional requirements to satisfy interchangeability as a higher regulatory standard.
In less strictly regulated areas, different evaluation and approval processes sometimes are applied, which in some cases may allow use of FO-DMTs without the requirement of demonstration of safety and efficacy comparable to that of the brand product.
What FO-DMTs are currently available for MS?
As of December 2023, approved FO-DMTs in the US include glatiramer acetate, dimethyl fumarate, fingolimod, mitoxantrone, and natalizumab. Aside from natalizumab, which is a biosimilar (monoclonal antibody), all other approved FO-DMTs are generics. In addition to generic oral fingolimod capsule, an orally disintegrating formulation of fingolimod is available as a separate non-generic product, but which is therapeutically equivalent to Gilenya.
Rituximab is a monoclonal antibody approved for use in hematological malignancies and rheumatological diseases. Several biosimilar versions have been approved. Although rituximab was studied in MS, formal registration for MS was not pursued. It is frequently used off-label in MS and other neuroinflammatory conditions based on mechanism of action shared with other approved anti-CD20 monoclonal antibodies, demonstrated efficacy in clinical trials, and accumulated clinical experience. As patent protection for MS DMTs expire, an increasing number of FO-DMTs are anticipated.
How do FO-DMTs compare to reference DMTs?
As the basis for approval, FO-DMTs need to be demonstrated to be highly similar to reference DMTs and are intended for use in the same manner. The expectation is for FO-DMTs to perform comparably to reference DMTs, without clinically meaningful differences.
Are FO-DMTs safe and effective?
Based on studies conducted to support approval in highly regulated jurisdictions such as the US, Canada, and Europe, FO-DMTs can be considered as safe and effective as the reference DMTs for the specified indications.
Does use of FO-DMTs require special monitoring?
Because FO-DMTs are considered comparable to the brand product, pre-treatment testing and on-treatment monitoring are the same. Similarly, if a DMT has a required Risk Evaluation and Mitigation Strategy (REMS) program, e.g., the Tysabri TOUCH program, a similar program would be required for FO-DMTs for that product.
Is it acceptable to switch from a reference DMT to an equivalent generic or biosimilar medication?
It is acceptable to switch from a reference DMT to an equivalent FO-DMT. Generics and biosimilars classified as interchangeable are eligible for substitution at the pharmacy level, but state laws may require additional prescriber authorization. Currently approved biosimilar natalizumab is not an interchangeable product, and its use is at the prescriber’s discretion. We recommend communicating such decisions between the person with MS, prescribing clinician, and pharmacist.
Is it acceptable to switch between same-class generic or biosimilar medication?
Switching FO-DMTs within the same class needs to be done with caution. Although FO-DMTs are considered equivalent to reference DMTs, there may be a greater difference in certain pharmacological characteristics between two distinct FO-DMTs within the same class, and which may translate into variability in clinical performance.
What are some of the recognized challenges with the use of FO-DMTs?
The incentive for use of FO-DMTs is to reduce healthcare costs. However, until there are several FO-DMTs for a particular DMT and resultant competition, there may not be a significant reduction in price. Also, the principal cost savings are for payors. Out-of-pocket costs may not be lower for individual patients. In fact, some sponsors of brand products have financial assistance programs, including to help cover medication co-pays, which may not be available for FO-DMTs. Similarly, some sponsors of brand products have well developed programs to assist with the start-up process, including patient education, and support programs to promote adherence. FO-DMTs sometimes do not have similar programs.
Long-term data, which exist for reference DMTs, may not be available for FO-DMTs, and continued pharmacovigilance should be encouraged and maintained. Registries and individual data should include the brand name of the FO-DMT, so distinct FO-DMTs can be readily identified. Such data enables periodic reassessment of clinical performance in a real-world environment. Obtaining data beyond the minimal regulatory approval requirements should guarantee continued product quality, safety, and effectiveness.
What is the nocebo effect and how to counter it?
Use of generics and biosimilars may be associated with a nocebo effect. Nocebo effect is the negative analog of the placebo effect. It describes a situation when negative expectations associated with a particular intervention leads to symptom worsening or side effects, but without a direct mechanistic link (the intervention is not the cause of reported negative effects, rather the negative expectations are). Nocebo effect may be present for medications, including FO-DMTs (Example: worsening symptoms are reported while taking an FO-DMT, but not the reference DMT, and which is likely due to negative expectations associated with use of a “low cost copy” of a drug). Strategies to counter the nocebo effect include education and shared decision-making regarding DMT choices.
Do Mellen Center clinicians support the use of FO-DMTs?
Typically, the incentive for use of FO-DMTs comes from payors. If prescription of a FO-DMT is required by a patient’s medical coverage, Mellen clinicians generally are supportive, recognizing the caveats discussed above. We only use or consider the use of those FO-DMTs which are approved in our jurisdiction of practice. In general, FO-DMTs perform as well as brand products. As for any DMT, we monitor effectiveness, safety, and tolerability. If incomplete disease control, safety issues, or intolerable side effects are noted or if the out-of-pocket financial issues for the patient arise, we advocate for use of the brand product or change in DMT.
Do Mellen Center clinicians support the use of generics for MS symptom management?
Besides DMTs, other treatments are used in MS primarily for symptom management. Symptoms such as spasticity, bladder or bowel dysfunction, depression, anxiety, fatigue, and insomnia are treated with medications which may also have generic products available. We support the use of generics for symptom management, with the same dosing and indications as the reference drug.
References
- Moss BP, Cohen JA. The emergence of follow-on disease-modifying therapies for multiple sclerosis. Mult Scler. 2019;25(12):1560-1565. doi:10.1177/1352458519845106
- Brownlee WJ, Wolf C, Hartung HP, et al. Use of follow-on disease-modifying treatments for multiple sclerosis: Consensus recommendations. Mult Scler. 2022;28(14):2177-2189. doi:10.1177/13524585221116269
- Greenberg B, Giovannoni G. A place for biosimilars in the changing multiple sclerosis treatment landscape. Multiple Sclerosis and Related Disorders. 2023;77:104841. doi:10.1016/j.msard.2023.104841
- Hartung DM. Health economics of disease-modifying therapy for multiple sclerosis in the United States. Ther Adv Neurol Disord. 2021;14:1756286420987031. doi: 10.1177/1756286420987031
