‘Patient-first, Science Based Regulatory Approaches for Insulins’

Dr. Sundar Ramanan, VP, Global Regulatory Affairs, Biocon,

Presented at the U.S. FDA Public Hearing on Increasing Insulins Access

Biocon Ltd. was among a handful of biopharmaceutical companies that presented at the U.S. Food and Drug Administration’s (FDA) public hearing “The Future of Insulin Biosimilars: Increasing Access and Facilitating the Efficient Development of Biosimilar and Interchangeable Insulin Products,” held at the FDA White Oak Campus in Silver Spring, Maryland on May 13, 2019.

Dr. Sundar Ramanan, Vice President, Global Regulatory Affairs at Biocon, presented on behalf of the Company at this public hearing organized by the U.S. FDA to receive inputs from industry experts on how to facilitate the development of insulin biosimilars and other interchangeable insulin products to address the soaring cost of these life-saving medications for people with diabetes.

Mylan, Eli Lilly and Diasome Pharmaceuticals were the other pharma companies that presented at the hearing, which was also addressed by representatives of pharma trade associations, patient groups and physician groups.

THE INSULIN CRISIS

Insulin prices in the U.S have tripled from 2002 to 2013, making this therapy unaffordable and thus inaccessible for large patient pools leading to a huge health crisis in the country.

There are more than 30 million diabetics in the U.S. and a significant number of them need access to insulins to survive. According to the American Diabetes Association, diabetes is the seventh-leading cause of death in the U.S.

There have been Senate and House of Representatives hearings on insulin prices, multiple lawsuits against insulin manufacturers and letters from lawmakers asking for explanations for continued price increases. Senators are now asking the FDA to make it easier to bring insulin biosimilars to the market.

It is expected that once biosimilars are approved, they will bring new competition to the insulin market and help provide affordable treatment options to patients with diabetes without compromising safety and effectiveness.

BIOCON’S MISSION

Biocon has been on a mission to enable affordable access to complex therapeutics for patients and to bring down the overall healthcare burden. The Company is driven by a passion to develop cost effective biosimilars that have the potential of benefitting a billion patients.

As a credible, global insulins player, Biocon has been addressing the needs of diabetes patients for over 15 years. The significant investments in developing and manufacturing a leading portfolio of recombinant human insulin (rh-insulin) and insulin analogs such as Glargine have led the Company to provide over 2 billion doses of insulin resulting in about 730 million patient days of safe exposure to its insulin products.

Biocon is keen to address the unmet patient needs of people with diabetes in the U.S.

CONSIDERATIONS FOR DETERMINING BIOSIMILARITY OF INSULINS

Dr. Ramanan, in his presentation Patient-first, Science Based Regulatory Approaches for Insulins, said the regulatory requirements for determining biosimilarity should be proportional to the complexity of a molecule. As insulins are simple proteins, the quality of a biosimilar vis-a-vis the reference product can be established through structural and functional characterization studies.  Unlike large proteins, insulins can be completely characterized thereby leaving “no unknown risks”. Next, unlike other proteins, the efficacy and safety of the biosimilar can be determined through in-vitro functional assays with high sensitivity. Thus, structural and functional analysis coupled with comparative pharmacokinetics / pharmacodynamics (PK/PD) studies can contribute to addressing the totality of evidence required for determining biosimilarity. The presence of a validated PD marker and the simplicity of the insulin molecule means there is very little residual uncertainty related to immunogenicity following the analytical characterization of biosimilar insulin. On immunogenicity, he said while some research has shown insulin treatment can lead to the production of antibodies in patients, it has not resulted in either loss of efficacy or safety incidences related to glycemia.   Therefore, only theoretical risks or known risks from the analytical similarity exercise can be addressed via a smaller more tailored clinical trials, Dr. Ramanan said.

On interchangeability, he proposed that all insulin biosimilars being approved by the FDA should be approved automatically as interchangeable without the need for any additional data.

SYNOPSIS OF THE PRESENTATION

CONDITIONS FOR BIOSIMILARITY

• Insulins are small and simple proteins-Insulins are simple proteins – can be completely characterized

In-vitro methods can adequately assess the safety of Insulins

• Efficacy & Safety can be determined using functional assays

Minimal residual uncertainty remains (Immunogenicity)

• Totality of evidence required for biosimilarity can be addressed via Structure-Function analysis and PK/PD Comparability. Minimal uncertainty remains on Immunogenicity.

Insulins Immunogenicity & Risk to Patient Safety

• Multiple studies have shown absence of a correlation between (Insulin Antibodies) IA’s & Insulin resistance
• Insulin Antibodies are not correlated with (1) loss of efficacy or (2) safety issues
• Product and Patient-related factors suggest that AIA’s don’t cause a loss of efficacy or safety issues

Recommendations to address any immunogenicity risks

• A single 300-patient study should be adequate to address any product and/or patient-related immunogenicity risks

Other considerations toward totality of evidence

• Products with multiple formulations: Immunogenicity assessment of the formulation with the highest theoretical risk is sufficient. Safety & Immunogenicity can be extrapolated to other formulations.
• Products with multiple concentration: Safety & Immunogenicity assessment of one concentration is sufficient, along with a PK/PD assessment for an additional concentration based on scientific justification.
• Safety & Immunogenicity data from clinical trials with a different reference product (for OTC products) should be considered toward the totality of evidence for biosimilarity

 

CONSIDERATIONS FOR INTERCHANGEABILITY

Only therapeutic proteins with OTC rating (r-Human Insulin)

Despite large differences in the Product Characteristics

• Under emergency situations the FDA allows rHI to be switched between manufacturers
• Effective Therapeutic Range is the Same & Wide (dosage is Identical, unit-per-unit basis)
• Designated as OTC by the FDA

No incremental risk for interchangeability

• No additional need for evidence between Biosimilarity & Interchangeability

Uniqueness of Insulins

• There are multiple reference products or biosimilars available to patients today, and these products are frequently switched with each other because of an OTC rating or other drivers, therefore:
• When a biosimilar is approved, it should be deemed as interchangeable to all the reference products

Unique scientific considerations for continuous infusion pumps

• All product related factors have been adequately addressed via totality of evidence for biosimilarity /interchangeability
• Product compatibility testing and Extractable/Leachable studies are adequate to ensure safety. No additional studies are needed.

 

PATIENT EXPERIENCE SHOULD ALLOW FOR A GREATER ACCESS TO BIOSIMILARS

• Patient experience data should be linked with clinical outcomes, i.e. safety, efficacy etc.
• Patient preference data, should be limited to clinical outcomes
• Policies should allow patient experience and/or patient preference data to be utilized toward enabling approval, access and/or adoption of biosimilars

FDA should enable fair, transparent, evidence based communication

Level playing field for both the reference product and biosimilars

• Any false and/or misleading information campaign should have meaningful consequences
• FDA must ensure that the promotional materials not include language that is suggestive or negative about biosimilars
• Any educational and promotional materials casting aspersions on the biosimilarity and/or interchangeability should be discouraged

Enhanced education on storage and handling should mitigate Loss of Efficacy (LoE)

• We request the FDA to discourage attribution of LoE to either the reference products, biosimilars or due to switching between the two, without convincing evidence

Patient-first, Science-based regulations ensure efficient development of biosimilar and interchangeable Insulins.

CONCLUSION

• Insulins are simple proteins and the regulatory requirements should be proportional to the complexity
• Residual uncertainty can be accurately identified and quantified
• Such residual uncertainty can adequately be addressed in a single clinical trial
• The totality of evidence required for a biosimilar or interchangeable insulin is the same
• Compatibility studies are necessary and sufficient to address any risks related to continuous infusion pumps
• Patient experience data should enable quicker access to biosimilars