With the advent of the Biologics Price Competition and Innovation Act of 2009 (BCPI Act), the possibility of additional competition in the biologics marketplace is moving closer to actuality. The BCPI Act, which creates an abbreviated pathway for demonstrating the biosimilarity of a biological product to a reference product, is part of the Affordable Care Act. Section 351(k) of the PHS Act establishes the requirements for applying for biosimilar status for a proposed interchangeable product. 

The FDA has now released five draft guidance documents, (see SIDEBAR 1. FDA’s Draft Guidance for Industry) which are designed to guide biologics manufacturers through the new process of demonstrating that a therapeutic biologic product is biosimilar to its reference product. The draft documents address myriad issues, from the science required to establish biosimilarity and manufacturing processes, to the biological product sponsor’s procedures for meeting with the FDA. The guidance documents include technical points, such as identifying differences in excipients that may affect product degradation or clinical performance and study design parameters for developing pharmacokinetic and pharmacodynamics data. The FDA is likely to release further guidance documents that will address the issues surrounding interchangeability, labeling, and exclusivity rights. 

The level of detail in these documents regarding the evidence needed to establish biosimilarity provides some insight into the potential cost of bringing a biosimilar to market, which of course will impact the ultimate pricing of the product. 

Pharmacy’s Role
Staying on top of the developments in this area can be challenging given the complicated nature of this subject, the novelty of the issue, and the fact that little information is disseminated to pharmacy. Because these guidance documents are still in the draft phases, until they are finalized, changes are likely. Nonetheless, they provide insights into some of the issues that will unfold as health systems consider the option of purchasing biosimilar products. 

While these guidance documents were not written for hospital pharmacists, they do illuminate key considerations for pharmacy directors who soon will be responsible for considering the addition of biosimilar products to their formularies. As the resident medication experts in the hospital, it is key that pharmacy follows the developments in this area and prepares to take a leadership role in guiding decision making around biosimilar products. 

Manufacturing Concerns
The FDA recognizes that differences in manufacturing processes between a sponsor’s proposed biosimilar and the reference product are likely and that those different processes could result in an altered protein, with a potential impact on the safety and/or effectiveness of the product. Currently, if a biologic manufacturer alters the manufacturing process for a given marketed product, the effects of the change must be assessed through testing and assays, as well as clinical and/or animal studies as appropriate, with the goal of demonstrating that the change will not adversely effect the safety or efficacy of the product. 

For a proposed biosimilar, demonstrating interchangeability will be more complex than assessing product changes made by one manufacturer. When a manufacturer alters their own manufacturing process, they do so under their established controls and acceptance parameters. In contrast, a proposed biosimilar will likely have a very different manufacturing process, including a different cell line, raw materials, equipment, processes, process controls, and acceptance criteria. As such, it is likely that the FDA will require more data to establish biosimilarity than they would to establish that a manufacturer’s product remains comparable after a manufacturing change to the pre-change product.



Postmarketing Safety Monitoring & Labeling
Just as postmarketing safety monitoring is a key aspect in ensuring the safety and efficacy of biologic products, robust postmarketing monitoring is expected to be a key component for any sponsor’s proposed biosimilar. It is expected that this monitoring will not take a standardized approach; rather, a specific plan will be developed for each product. 

The postmarketing safety monitoring will begin with any concerns surrounding the reference product and its class. Next, it will incorporate any issues specific to the proposed product. It is important that the monitoring plan be sufficiently detailed to identify adverse events that were not previously associated with the reference product. By its nature, pre-approval testing encompasses smaller populations than will receive an approved product. This larger population presents the opportunity to identify particularly rare safety risks. Consider immunogenicity, for example, as this rare but potentially serious side effect can be difficult to detect in studies with small sample sizes. As such, postmarketing safety monitoring is likely to be a key component for many proposed biosimilars. It is expected that the FDA will require either postmarketing surveillance and/or postmarketing studies (in many cases). 

To date, the FDA has provided somewhat cursory information on labeling requirements for proposed biosimilars. The guidance documents propose that the labeling include all necessary information for making prescribing decisions. In addition, the labeling should clearly indicate that the product is approved as a biosimilar to the reference product for which indication(s) and which route of administration(s). Likewise, the label must state whether or not the product has been deemed interchangeable with the reference product. 

Both postmarketing safety monitoring and product labeling are areas where pharmacy will need to play a key role to continually ensure patient safety, and more information is expected to be forthcoming from the FDA on these topics.

Categorizing Biosimilarity
The latest guidance from FDA, Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product, provides some insight into how the FDA may ultimately determine biosimilarity, and this is particularly helpful for pharmacists. Extensive analytical characterization will be required on the part of the product’s sponsor. Should that data reveal differences between the reference product and the proposed biosimilar, those differences and any potential effect they could cause must be characterized. In some cases, additional studies will be required to demonstrate the effect of these differences, and in other cases, the differences in analytical characterization may result in a recommendation to not continue the development of the proposed product through this pathway.  

Further clarifying this position, the FDA proposes four classifications for proposed biologics within the development continuum: 

Not Similar: A proposed biosimilar may be characterized as not similar due to certain differences in the results of the analytical characterization. At that point, further development through the 351(k) regulatory pathway is not recommended unless, for example, modifications are made to the manufacturing process for the proposed biosimilar product that are likely to lead to a highly similar biological product. 

Similar. A proposed biosimilar may be characterized as similar, indicating that the sponsor needs to present additional information to determine whether the product is highly similar to the reference product. For example, additional analytical data or other studies may be deemed necessary to determine if observed differences are within an acceptable range to consider the proposed biosimilar product to be highly similar to the reference product.

Highly Similar. A proposed biosimilar may be deemed highly similar if it meets the statutory standard for analytical similarity given the results of the comparative analytical characterization. The product sponsor would then conduct targeted and selective animal and/or clinical studies to resolve any residual uncertainty and demonstrate biosimilarity. 

Highly Similar with Fingerprint-Like Similarity. A proposed biosimilar may be characterized as highly similar with fingerprint-like similarity if it meets the statutory standard for analytical similarity “based on integrated, multi-parameter approaches that are extremely sensitive in identifying analytical differences. These results of these fingerprint-like analyses permit a very high level of confidence in the analytical similarity of the proposed biosimilar and the reference product.”1 The product sponsor would then conduct targeted and selective animal and/or clinical studies to resolve any residual uncertainty and demonstrate biosimilarity. 

This last category of fingerprint-like similarity foreshadows the FDA’s likely position on interchangeability. An exacting process will be necessary to determine the level of biosimilarity required for possible substitution for a reference product at the pharmacy level.

Conclusion
Certainly it is important for pharmacy to stay abreast of developments as the process for biosimilar approval matures. Perhaps it is even more important for pharmacy to take an active role in this exciting change. Not only is there value in monitoring the new guidance documents being issued by the FDA, but also consider taking a place at the table by adding your voice to the comments. Pharmacy will be impacted by the labeling rules and will most certainly play a role in postmarketing safety monitoring; thus, becoming involved now will allow you to have an impact in this rapidly developing field. Today’s involvement will leave you better prepared to make the formulary and prescribing decisions you are certain to face in the near future.

Reference

1. Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product. May 2014 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM397017.pdf. Accessed 7/1/14.

Deanne Halvorsen is the editorial director at Ridgewood Medical Media, publishers of Pharmacy Purchasing & Products and Medical Lab Management magazines. She can be reached at dhalvorsen@ridgewoodmedia.com.

SIDEBAR 1
FDA’s DRAFT GUIDANCE for Industry

1. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product
February 2012
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf

2. Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product
February 2012
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291134.pdf

3. Q&As Regarding Implementation of the BPCI Act of 2009
February 2012
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm259797.htm

4. Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or Applicants 
March 2013
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM345649.pdf

5. Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product  
May 2014
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM397017.pdf

FDA Definitions

• Biological product means “a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any chemically synthesized polypeptide), or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings.”¹
• Biosimilar or biosimilarity means that “the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components,” and that “there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product.”² 
• Chemically synthesized polypeptide means any alpha amino acid polymer that is a) made entirely by chemical synthesis and b) is less than 100 amino acids in size. 
• Immunogenicity is defined as an immune response to the biological product that may result in immune-mediated toxicity and/or lack of effectiveness. 
• Protein means any alpha amino acid polymer with a specific defined sequence that is greater than 40 amino acids in size. 
• Reference product means the single biological product licensed under section 351(a) of the PHS Act against which a biological product is evaluated in a 351(k) application.³ 

References

1. Section 7002(b)(2) of the Affordable Care Act, amending section 351(i)(1) of the PHS Act. 
2. Section 7002(b)(3) of the Affordable Care Act, adding section 351(i)(2) of the PHS Act. 
3. Section 7002(b)(3) of the Affordable Care Act, adding section 351(i)(4) of the PHS Act. 

Submit Comments by August 12, 2014
The FDA welcomes comments on the draft guidance, Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product. Comments can be submitted electronically through August 12, 2014 at: http://www.regulations.gov 
Reference: Docket No. FDA–2014–D–0234