Different approaches to Biomarkers

Intercept Pharmaceuticals, a U.S.-based biotech firm founded in 2002, has focused on developing novel treatments for chronic liver diseases. Its flagship product, Ocaliva (obeticholic acid), was designed to treat primary biliary cholangitis (PBC), a rare autoimmune liver disorder that can lead to liver failure. While Ocaliva offered hope for patients with limited treatment options, the road to regulatory approval in the U.S. and Europe revealed stark differences between the FDA and EMA, particularly in terms of data requirements and safety concerns.

A Swift FDA Approval

Intercept sought approval for Ocaliva in the U.S. first, given the pressing need for therapies that could treat PBC more effectively than the standard ursodeoxycholic acid (UDCA), which many patients do not tolerate or do not respond to. In May 2016, the FDA granted accelerated approval for Ocaliva based on surrogate endpoints, specifically reductions in alkaline phosphatase (ALP), a marker of liver damage. The FDA accepted ALP reduction as a reasonable proxy for improvement in liver function, given the lack of long-term treatment alternatives for PBC patients.

However, the FDA’s approval came with conditions. The agency required post-marketing studies to further assess the long-term safety of Ocaliva, particularly given the drug’s potential to raise cholesterol levels and its risk of causing liver-related adverse events. While the approval allowed Intercept to launch Ocaliva in the U.S., it was under strict monitoring to ensure that the benefits outweighed any potential risks.

EMA’s Cautious Approach

While Intercept found relatively quick success in the U.S., the European road to approval proved to be much more complex. The EMA, while similarly recognizing the need for new PBC treatments, expressed concerns about the safety profile of Ocaliva. The agency’s focus was on the long-term risks, particularly in terms of liver function deterioration and cardiovascular safety due to increased cholesterol levels. The EMA demanded more data before granting approval, delaying Ocaliva’s entry into the European market.

In December 2016, Ocaliva was finally approved by the EMA, seven months after its U.S. counterpart. However, the delayed approval came with significant conditions. The EMA required additional long-term efficacy and safety data, particularly on how well Ocaliva could prevent the progression of liver damage to more severe stages, such as cirrhosis. Furthermore, the EMA placed restrictions on Ocaliva’s use, recommending it primarily for patients who had an inadequate response to UDCA or could not tolerate it.

Regulatory Delays and Impact

The differing regulatory stances of the FDA and EMA not only delayed Ocaliva’s availability in Europe but also impacted Intercept’s global strategy. In the U.S., Ocaliva was quickly positioned as an important therapy for PBC patients, while in Europe, its market entry was delayed as Intercept had to meet the EMA’s more stringent requirements for long-term safety data.

These delays had a tangible commercial impact on the company. The extended time to market in Europe meant that Intercept could not immediately capitalize on Ocaliva’s success in the U.S. Moreover, the EMA’s requirement for additional studies significantly increased the costs and complexity of bringing the drug to European patients. In contrast, the FDA’s acceptance of surrogate endpoints allowed for a faster launch in the U.S., although post-marketing commitments remained.

Lessons Learned: Anticipating Regulatory Differences

The regulatory experience of Intercept Pharmaceuticals with Ocaliva highlights the challenges that biotech companies face when navigating the different evidentiary standards of the FDA and EMA. While the FDA’s accelerated approval pathway allowed Ocaliva to reach the U.S. market quickly, the EMA’s insistence on long-term safety data delayed the drug’s availability in Europe.

For companies seeking to bring new therapies to global markets, the key lesson is the importance of clinical trial design that anticipates the differing demands of regulatory bodies. By integrating both short-term surrogate endpoints (to satisfy the FDA) and long-term clinical outcomes (to meet EMA requirements) into clinical trials from the outset, companies can reduce delays and avoid costly post-authorization commitments.

Intercept’s journey with Ocaliva shows that early strategic planning around regulatory requirements can significantly reduce time to market and improve global patient access. For biotech firms expanding into Europe, understanding these regulatory nuances is critical to success.