The Core Definition: A Novel Mechanism of Action
At its heart, a drug is considered 'first-in-class' (FIC) when it is the first to be approved that operates via a completely new and unique mechanism of action (MoA) to treat a particular condition. This differs fundamentally from so-called 'me-too' drugs, which are later entries into the market that share the same MoA as an existing medication. Instead of improving on an existing treatment approach, a FIC drug breaks new ground, affecting a newly identified biological pathway or targeting an previously undiscovered target. For patients, this is often a major breakthrough, especially for diseases that have no effective treatments, limited options, or existing therapies with unacceptable side effects.
For example, the discovery of statins revolutionized the treatment of high cholesterol. While multiple statin drugs exist now, the first statin to be approved was a first-in-class drug that pioneered the approach of inhibiting the HMG-CoA reductase enzyme. Subsequent statins that were developed followed this same mechanism of action. The FDA does not recognize 'first-in-class' as a formal regulatory category, but it tracks these novel therapies due to their potential impact on medicine.
The First-in-Class Landscape: Risks and Rewards
The development of a first-in-class drug is a high-stakes, high-reward endeavor. For the pharmaceutical company, a successful FIC launch can establish market leadership and secure valuable intellectual property rights. However, the path is fraught with uncertainty.
Rewards of First-in-Class Drugs
- Therapeutic Breakthroughs: FIC drugs often provide the first effective treatment option for conditions with high unmet needs, offering hope to patients where none existed.
- Market Leadership: Being the first to market with a new mechanism can grant a significant first-mover advantage, potentially leading to higher pricing and market share, especially in specialized areas.
- Stimulates Future Innovation: A successful FIC drug can validate a new target, signaling to other innovators that the area is viable and stimulating further research and development within that therapeutic space.
- Expedited Regulatory Review: Many FIC drugs receive special designations from regulatory bodies like the FDA, such as Breakthrough Therapy or Orphan Drug status, which can speed up the development and review process.
Risks and Challenges of First-in-Class Drugs
- Clinical Uncertainty: Due to the novel MoA, there is less clinical experience and more uncertainty regarding long-term safety and efficacy compared to later-in-class drugs. Unforeseen side effects can emerge after market approval, leading to restrictions or even withdrawal, as seen with the diabetes drug troglitazone.
- Higher Costs and Lower Success Rates: Developing a FIC drug on an unvalidated target is riskier. Success rates for FIC drugs are lower than for drugs built on established targets, and development costs are typically higher.
- Pricing Scrutiny: The high price of many novel therapies can lead to intense scrutiny from payers and health systems, and later entrants with improved profiles can put downward pressure on pricing.
First-in-Class vs. Best-in-Class: A Key Distinction
While being first is often prestigious, it does not guarantee long-term success. A later entrant, or 'follower' drug, can often build upon the pioneer's work and develop a best-in-class (BIC) therapy. A BIC drug is one that demonstrates superior therapeutic value—either through improved safety, better efficacy, or more convenient dosing—than other drugs in the same class. Many blockbuster drugs have achieved their status by being best-in-class, not first-in-class, as they refined the therapeutic approach and offered a better profile for patients and physicians.
| Criterion | First-in-Class (FIC) | Best-in-Class (BIC) |
|---|---|---|
| Mechanism of Action | Novel and unique; pioneers a new therapeutic approach. | Same as the FIC drug but with improvements. |
| Risk/Uncertainty | Higher risk due to novel MoA and limited clinical experience. | Lower risk, as the target and MoA have been validated. |
| Development Effort | Significant effort required to prove efficacy and safety for the first time. | Builds on the scientific and clinical experience of the FIC drug. |
| Clinical Evidence | Based on initial trials; long-term data is absent at launch. | Benefits from and can build upon existing evidence in the class. |
| Market Position | First to market; potential for significant advantage if competitors are slow. | Later entrant; captures value through differentiation and superior profile. |
| Examples | Infliximab (Remicade) for rheumatoid arthritis. | Humira (adalimumab), a later anti-TNF drug with a more convenient dosing schedule, surpassed earlier entries. |
Notable Examples of First-in-Class Breakthroughs
- Mounjaro (tirzepatide): Approved in 2022, this is a first-in-class medication for type 2 diabetes. It works by activating not just the glucagon-like peptide-1 (GLP-1) receptor but also the glucose-dependent insulinotropic polypeptide (GIP) receptor, a unique dual-mechanism approach that led to improved glycemic control.
- Tepezza (teprotumumab): Approved in 2020 for Graves' ophthalmopathy, an autoimmune condition affecting the eyes. It was the first drug approved for this specific indication and works by inhibiting the insulin-like growth factor 1 receptor (IGF-1R).
- Tzield (teplizumab-mzwv): This was a groundbreaking approval in 2022 to delay the onset of Stage 3 type 1 diabetes in at-risk individuals. Its mechanism is a monoclonal antibody that intercepts the body's autoimmune attack on insulin-producing cells.
The Broader Impact of First-in-Class Drugs
First-in-class drugs serve as the engine of pharmaceutical innovation. They advance medical understanding by proving new biological targets are viable, and in doing so, they expand the range of therapeutic possibilities. The entry of an FIC drug can galvanize further research and development within a disease area, as it provides a proof-of-concept that subsequent researchers can refine or build upon. This dynamic, however, highlights the need for a balance between encouraging risky, ground-breaking research and ensuring the development of incrementally improved therapies. The ultimate goal is to provide the safest and most effective medicines for patients, regardless of whether they were first, best, or somewhere in between.
Conclusion
Being first-in-class in pharmacology is a hallmark of true innovation, representing a drug with a novel mechanism of action that addresses a medical need in a new way. These pioneer drugs carry the inherent risks of breaking new scientific ground but also offer the potential for life-changing therapeutic breakthroughs. They set the stage for subsequent follow-on drugs, some of which may become the 'best-in-class' standard of care by improving on the original concept. The continuous cycle of first-in-class discovery and subsequent refinement ensures a vibrant pharmaceutical landscape focused on delivering ever-improving treatment options for patients worldwide.
