Drug makers butt heads on US FDA's proposed biosimilars guidances

There were few inside the biopharmaceutical industry that didn't have something to say this week about the US FDA's proposed guidance documents intended to help makers of biosimilars understand the agency's expectations about developing the products and how to interact with regulators through the approval process – with even the government of the Republic of Korea chiming in, although its submitted comments contained more inquiries than recommendations.

Drug makers and groups that rushed to meet the agency's 16 April midnight deadline to submit comments to regulators on three draft biosimilar guidances issued on 9 February appeared eager for their tweaks, if not all-out changes, to be adopted by the agency (scripintelligence, 10 February 2012).

Amgen urged the FDA to "candidly communicate its expectations" in its final guidances and to "acknowledge what we know today and what we do not yet know".

"The science of biotechnology has come a very long way in three decades, but it would be detrimental to patient safety and undermine the goal of achieving a successful approval pathway if policy decisions were premised on aspirations rather than achievements," the Thousand Oaks, California-based biotech giant insisted.

Amgen said the FDA should use more "precise language" in its final guidances whenever feasible.

"We recognize that regulatory standards and expectations must be flexible enough to accommodate the uniqueness of each biologic and to adapt to scientific and technical advances," the company said. "The wide degree of flexibility and lack of clarity reflected in the draft guidances, however, risk undermining the objective of providing meaningful guidance to industry. Enhancing the specificity of the final guidances would improve transparency and facilitate the timely development of safe, pure and potent biosimilars."

The Biotechnology Industry Organization (BIO), which attested that its recommendations were "grounded by the specific hands-on experience" of its member companies, was among those that objected to the use of the word "should" in the FDA's guidances for fundamental requirements expected to be performed – a word the biotech lobbying group said implies that action does not necessarily need to be taken.

"It is important to be clear about the fundamental requirements, and what might be modified on a case-by-case basis," BIO said.

For instance, the group said, rather than stating in its Draft Guidance for Industry on Scientific Considerations in Demonstrating Biosimilarity to a Reference Product that a manufacturer "should" consider the complexities of protein products and related scientific issues when it designs a development programme to support a demonstration of biosimilarity, BIO said the word "should" ought to be replaced in that statement with "is expected to" to convey the criticality of certain studies that are necessary for performing a biosimilarity assessment.

Roche unit Genentech noted the FDA uses other phrases, like "will need to," "FDA recommends," or "are fundamental components" to convey clearer expectations for certain data and information.

BIO also said more collaborative statistical research into methods of establishing biosimilarity – and, later, interchangeability – criteria "is essential".

While BIO commended the FDA for "appropriately acknowledging the complexities of protein products," the group said the agency needs to address more clearly and specifically the issue of when and whether data comparing a prospective biosimilar to a non-US-licensed comparator may be useful in supporting marketing applications for those products, known as 351(k)s.

BIO emphasized in its comments that the Biologics Price Competition and Innovation Act – the legislation in the 2010 health reform law that created the pathway giving the FDA the authority to approve biosimilars – mandates that those products be evaluated only against one innovator reference product, known as 351(a)s.

While BIO said it agrees with the FDA taking a "stepwise approach" for demonstrating biosimilarity – which regulators said can include a comparison of the proposed product and the reference medication with respect to structure, function, animal toxicity, human pharmacokinetics and pharmacodynamics, clinical immunogenicity and clinical safety and effectiveness – the biotech lobbying group said it was concerned that section of the guidance clashes with the language of the statute.

"It appears as though the requirements for clinical data are a 'residual requirement,' and triggered only if there are gaps or insufficiencies" in the analytical, pharmacokinetic (PK) or pharmacodynamic (PD) data and the safety package, BIO stated.

In contrast, the statute is set up such that clinical trials are required, with an affirmative finding by the FDA to determine those studies are not necessary.

BIO insisted that immunogenicity studies comparing the proposed biosimilar with the US-licensed reference product "should always" be conducted and "should be of sufficient duration" to assess the effects of immunogenicity on PK, biodistribution, safety and efficacy, and that testing should take into consideration the nature and severity of immune responses.

The group said "additional clarity is warranted" to describe fully the type of bridging studies and associated confidence intervals that could support biosimilar approval.

The FDA, BIO said, should address scenarios where comparator data and bridging studies would not be sufficient to support licensure of a biosimilar or where additional bridging information would presumptively be required, such as where the non-US comparator product has a different strength, dosage form, or route of administration.

The group also objected to the use of non-US comparator data for complex biological products.

Swiss drug maker Novartis, the parent company of biosimilar developer Sandoz, noted that the FDA has acknowledged it is unethical to repeat or require unnecessary studies for any product, not just biosimilars.

"Just as the agency only requires necessary studies for originator products, the same should apply for biosimilars with all use of animals and people, in particular, minimized," Novartis said in its comments. "As a basic premise for the development of any product, the minimum studies that enable safe pure and potent products to reach patients should be requested, and consideration given to what, if any, of the studies actually impact the nature of the product approved."

For a biosimilar, the Basel, Switzerland-based drug and vaccine maker said, "only up to the point of the highly similar designation is the product itself subject to any alteration".

After that point, it contended, "good manufacturing control require that the product is made very consistently to the same, stringent release criteria. As such, an interchangeable biosimilar is simply a biosimilar on which additional studies have been conducted, and within the development of the biosimilar itself the same reasoning applies."

Novartis said it is critical to consider whether each requested study results in a better biosimilar reaching patients, or merely one on which additional, likely resource-intensive, studies have been done.

"This will be particularly true of those biosimilars that have already been approved in other highly regulated markets," the firm said.

US generic giant Mylan charged that the FDA's draft guidances, as currently written, "create an unnecessarily?higher bar" for biosimilars than is applied to brand biologics that meet the "highly similar" standard after having undergone process and formulation changes, and "thus does not establish a realistic and workable pathway" to interchangeability.

Mylan asserted that the guidances "have the effect of creating an unlevel playing field" between originator biologics and biosimilars.

Some of the "apparent inconsistencies" between the requirements in the draft guidances and the FDA's longstanding science-based biologics regulations "could impede development and approval of equally safe and effective" biosimilars, and thereby defeat the purpose of the law that made the approval pathway possible, Mylan argued.