Biosimilars Update: FDA Releases “Purple Book”; Two Companies File Biosimilar Applications, Industry Responds to Draft Guidance

Vaccines, allergy shots, blood components, and gene therapies are examples of biological products. Most biologics are produced in living organisms, such as plant or animal cells, whereas small molecule drugs (most pharmaceuticals) are typically manufactured through chemical synthesis. The inherently complex nature of biologics makes them expensive to develop and impossible to copy in the manner traditionally associated with the approval of generic drugs.

BioSIMILAR, not BioEQUIVALENT

Enter “biosimilars,” which the Food and Drug Administration (FDA) defines as biological products that are highly similar to an already approved biological product, “notwithstanding minor differences in clinically inactive components, and for which there are no clinically meaningful differences between the biosimilar and the approved biological product in terms of the safety, purity, and potency.”

The patents of a growing number of biologic medicines have already expired or are due to expire soon, which has led to an increased interest in the development of “biosimilars.”  However, as FDA’s ambiguous definition illustrates, the exact process for entering the market is far from clear.

Expediting the Biosimilar Pathway

The Affordable Care Act included an abbreviated approval pathway for biological products that are demonstrated to be “highly similar” (biosimilar) to an FDA-approved biological product. This pathway is provided in the part of the law known as the Biologics Price Competition and Innovation Act (BPCI Act), which is Section 351(k) of the Public Health Services (PHS) Act. In May, FDA came out with a 17-page draft guidance, which offers specific steps that companies looking to file a 351(k) biosimilar application should consider. We wrote about this draft in detail here.

In that draft, FDA recommended that companies compare the quality attributes of the proposed biosimilar product with those of the reference product using a meaningful fingerprint-like analysis algorithm. Depending on what differences those analyses find, FDA will file each submitted treatment into one of four tiered categories: 

• Highly similar with fingerprint-like similarity – the proposed biosimilar is deemed nearly identical to the reference product, based on multi-parameter approaches that are extremely sensitive. Such drugs would need only “targeted and selective” further study to demonstrate their biosimilarity.
• Highly similar – the proposed biosimilar product meets the statutory standard for analytical similarity, but is not as similar as the above category;
• Similar – additional analytical data or other studies are needed to determine if the products are indeed highly similar; 
• Not similar – the proposed biosimilar is not actually similar, according to FDA; further progression through the 351(k) pathway is not recommended.

Industry members seek more clarity

Three major industry organizations submitted comments on this guidance, saying in letters to the agency that it could let “copycat” products be sold without fully demonstrating safety and effectiveness. The organizations are the Biotechnology Industry Organization (“BIO”), the Pharmaceutical Research and Manufacturers of America (“PhRMA”), and the Generic Pharmaceutical Association (“GPhA”)

As reported by FDA Life, PhRMA, GPhA, and BIO were concerned with the four parameters the draft guidance sets forth. If the FDA insists on preserving the categories within the guidance, it should eliminate “vague and confusing” definitions that make it unclear how regulators will decide which classification to apply, PhRMA wrote.

BIO also voiced concerns with the four categories. “BIO does not find it clear from the Draft Guidance what type or scope of information is needed to differentiate a ‘similar’ molecule from one that is considered ‘highly similar’ or ‘highly similar with fingerprint-like similarity.’” They specifically questioned FDA’s statement that a product merely deemed similar, and therefore not comparable enough to qualify as a biosimilar, could be deemed highly similar if “justified with additional data.” This additional testing could “expose human subjects to an experimental therapy that had not met the statutory analytical threshold of ‘highly similar,’” BIO wrote.

The “Purple Book”

An application filed by a generic pharmaceutical manufacturer under the Hatch-Waxman Act must demonstrate that the active ingredient of the generic drug is the same as that of a drug that has been previously approved by the FDA. The publication Approved Drug Products with Therapeutic Equivalence Evaluations, commonly known as the Orange Book, which since 1980 has published all pharmaceutical drug products that FDA has approved or have not been withdrawn due to issues of safety or efficacy. Click here for the 2014 version.

Now, the FDA has announced the Purple Book, the biopharmaceutical edition. The Purple Book lists biological products, including any biosimilar and interchangeable biological products licensed by FDA under the Public Health Service Act (the PHS Act). The lists include the date a biological product was licensed under 351(a) of the PHS Act and whether FDA evaluated the biological product for reference product exclusivity under section 351(k)(7) of the PHS Act.

According to FDA, the Purple Book will also enable a user to see whether a biological product licensed under section 351(k) of the PHS Act has been determined by FDA to be biosimilar to or interchangeable with an already-licensed FDA biological product.

“Biosimilar and interchangeable biological products licensed under section 351(k) of the PHS Act will be listed under the reference product to which biosimilarity or interchangeability was demonstrated,” FDA states.

Separate lists for those biological products regulated by the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) will be updated periodically.

Two Drugs on the 351(k) Pathway

The Purple Book currently has no biosimilars listed—which makes sense given that there are none on the market. That may change soon. Two companies have filed biosimilar applications in the US using the abbreviated 351(k) pathway described above.  

Alexander Gaffney of Regulatory Affairs Professionals Society (RAPS) has followed this issue closely, writing that on July 24, Sandoz filed the first-ever biosimilar application using the 351(k) pathway for its biosimilar, Zarzio. The reference product for Sandoz’ biosimilar is Amgen’s Neupogen, a biologic used to reduce infection risks in cancer patients under chemotherapy. Sandoz released a media statement noting they are a “global leader in biosimilars with over 50% share of the global biosimilars market.”

On August 11, South Korean biopharmaceutical manufacturer Celltrion also announced they would be filing an application for FDA approval for their drug Remsima, its biosimilar version of Jannsen’s Remicade (infliximab).

These two companies are charging ahead down the new 351(k) pathway, but it will be interesting to see how FDA defines “similarity” in practice, considering their entire draft guidance depends on how “similar” the proposed biosimilar is to the reference product. Both biosimilar products are approved in many countries outside of the US. 

The Biosimilar Naming Issue

Zarzio and Remsima are also the first two drugs to tread the naming issue regarding biosimilars, RAPS points out. The International Nonproprietary Name (INN) is the official generic name given to a pharmaceutical’s active ingredient by the World Health Organization (WHO), and it applies to each product globally. Thus, products with the same active ingredient have always shared the same INN, even in different countries.

In Europe, biosimilars have been approved using the same INN as the reference biologic, but there is disagreement stateside as to whether this is the best option. Wall Street Journal provided a nice summary of the two issues at hand: “Brand-name drug makers and biotechs want biosimlars (sic) to have unique or generic names to distinguish the medicines from the original biologics. They argue that different names would make it easier to track adverse events.” On the other hand, “[g]eneric drug makers believe a new naming standard may confuse health care providers as they sort out whether the medicines are really the same and attempt to verify dosing and regiments. And they maintain side effects can be traced through national drug codes and lot numbers.”

“They also argue that brand-name drug makers and biotechs are maneuvering to blunt competition before biosimilars are widely used in the U.S. Drug makers from on both sides of the debate have petitioned the FDA to adopt their respective positions.”

FDA reportedly has sent its naming guidance to HHS for approval, according to WSJ, so we will be interested to see what FDA lands on.