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BAOJ Clinical Trials Prashant A Pandya, Clinical Trials 2017, 3: 1 3: 014

Review

Program Management strategies in Bio-similar Development & Commercialization Prashant A Pandya* *GM-Program Management, CRS, Navi Mumbai, India

Abstract The biosimilar market is projected to be a multi-billion dollar segment in the next 10 years and having significant impact on pharmaceutical industry. “Comparability studies” are the foundation of Biosimilar development which involves a head to head comparison with reference medicine product which is tailor made for each product. It is important to design biosimilar clinical development plan keeping focus on patient enrolment and appropriate clinical end points. Commercialization strategies must optimize market uptake of biosimilars as regulations are still evolving hence it is vital for the companies to quickly modify biosimilar development strategies matching with the regulatory scenario. Keywords: Program Management; Project Biosimilar; Drug Development; Strategies

Biologics which prohibits other parties for set period of time before biosimilar application can approve. Figure: 1.0: Comparison of data requirements

Management;

Introduction[1,2] Biosimilar development is currently at peak and expected to grow further due to an ever-increasing pressure to reduce healthcare costs and patent expiry of high-value biologics innovator. Treatment with biologic cost around $1,00,000- 4,00,000 a year to patient. Many companies have heavily invested in biosimilar development however there are unique development and commercialization challenges in bio similar hence requiring detailed clinical development plan including better defined regulatory pathways and information about market access. Biosimilar is biologic that is showing ’exactly similar” safety and effectiveness to another biologic drug approved by FDA/EMA having only difference allowed are in non-active ingredients. They are allowed to market only after data exclusivity has expired for the reference biological medicine (after 10 years). Biosimilar is having same posology and route of administration like reference medicine. The majority of biologics currently in market contain active substance made form protein having different structural complexity and size ( e.gMaonoclonal antibodies, Coagulation factors, Growth hormones etc).There is significant cost saving by use of biosimilar. Currently, data exclusivity or data protection is allowed to innovator Clinical Trials, an open access journal

Source: European Medicines agency Guidelines.

As mentioned in Fig.1.0, during biosimilar drug development comparative clinical studies with reference medicine is needed along with comparative quality studies. Rest of the requirements are same like reference medicine.

History[1-5] The European medicine agency (EMA) was the first to define regulatory pathway for the Biosimilar development in 2005 followed by world health organization(WHO) and several other regulatory authorities. EU approved the first biosimilar in 2006 (Omnitrope *Corresponding author: Prashant A Pandya, GM-Program Management, CRS, Navi Mumbai-400701, India, Tel: +91-9967017172; E-mail: [email protected] Rec Date: July 27, 2017, Acc Date: August 09, 2017, Pub Date: August 10, 2017. Citation: Prashant A Pandya (2017) Program Management strategies in Bio-similar Development & Commercialization. Clinical Trials 3: 014. Copyright: © 2017 Prashant A Pandya. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Volume 3; Issue 1; 014

Citation: Prashant A Pandya (2017) Program Management strategies in Bio-similar Development & Commercialization. Clinical Trials 3: 014.

(somatropin) was the first product approved in the EU as a biosimilar) and till now EU has approved highest number of biosimilars. Of more than 35 biosimilars approved in the EU to date, none has been withdrawn or suspended for reasons of safety or efficacy. In 2012, FDA also issued draft biosimilar guidelines having scientific consideration and Q&A documents. Guidelines recommends to use stepwise approach covering analytical, preclinical and clinical (PK/PD, Efficacy and immunogenicity assessment).The first biosimilar product (Zarxio) was approved by FDA approved in March 2015.Zarxio was a biosimilar to Neupogen, which is indicated for the treatment of patients cancer receiving myelosuppressive chemotherapy. Biosimilars are approved according to the same standards of pharmaceutical quality, safety and efficacy that apply to all biological medicines approved in the EU/FDA. In addition there is no specific Pharmacovigilance requirement, it monitored through same way of other Biologics. Figure 2.0: Amount of Characterization in Biosimilar development.

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Table 1.0: List of approved Biosimilar Biologic Adalimumab Calcitonin Enoxaparin sodium Epoetin alpha Epoetin zeta Etanercept Filgrastim (G-CSF) Follitropin alpha (FSH) Glucagon Hyaluronidase Infliximab Insulin glargine Rituximab Somatropin Teriparatide

European Union Approved Approved Approved Approved Approved Approved Approved Approved Approved Approved Approved Approved

United States Approved Approved Approved Approved Approved Approved Approved Approved Approved

Source: Quintiles IMS

Program Management in Biosimilar Development[1,6-18] The Project Management Life Cycle has five phases. Dividing program management efforts into these five phases can help to accelerate Biosimilar development.

Source: Raymond Donninger, Analysis of characterization of biosimilars versus new biologic entities (NBEs), BioPharm International

As mentioned in Fig 2.0, There is a need for more extensive characterization for biosimilars than for innovator drugs. The trend in the industry is that analytical technology advances will continue at the same pace and will allow for more accurate physico– chemical and biological characterization, which may provide more guidance to nonclinical, pharmacokinetic/pharmacodynamic, and clinical studies.

Clinical Trials, an open access journal

1- Strategies during initiation stage of biosimilar development: An idea for a project will be carefully examined to determine whether or not it benefits the organization and realistically be completed. Below are the key strategies useful during Initiation stage of Biosimilar development. • Identify requirements for every intended biosimilar market. • Focus on minimizing the costs and timing of clinical development and maximizing the commercial success



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• It is important to list number of studies needed during clinical development including need to conduct pediatric as per Pediatric Research Equity Act (PREA).

• Prepare robust risk management plan (RBM) tailored for each biological medicines based on knowledge and experience gained from the reference product.

• Immunogenicity is potential concern for all biological medicine because of intrinsic ability of protein to cause unwanted immune response hence it is important to design clinical Immunogenicity studies and allocate budget.

• Engage efficient regional Contract research Organization (CRO) to boost patient enrolment.

• Try to use existing (available) generated data as much as possible or use as a supportive while filing regulatory application. • Prior regulatory consult is recommended before conducting “Interchangeability study orspecific Phase 3 switching studies” to prove efficacy and safety of biosimilar product. 2. Strategies during planning stage of biosimilar development A project plan, project charter and/or project scope may be put in writing, outlining the work to be performed. During this phase, company should prioritize the project, calculate a budget and schedule, and determine what resources are needed. Below are the key strategies useful during planning stage of Biosimilar development. • Develop stakeholder engagement plan at the start of clinical development. • Develop comprehensive Global regulatory plan that can be leveraged to satisfy regulators in each potential market. • Develop robust clinical trial protocol having right clinical end points and biomarkers to predict clinical efficacy. Design adequately powered randomized, double blind, parallel group study having efficacy end points to measure pharmacological activity. • Use adaptive study design, Biomarkers, Surrogate endpoints or develop staggered study design.Unlike conventional clinical trials, comparative clinical trials are needed to demonstrate safety and efficacy hence there is no need to focus on hard endpoint, howeverfocus in needed by using sensitive endpoints to find product related difference. • Selection of primary indication to demonstrate clinical similarity is critically important during clinical development plan as data extrapolation is possible getting approval to additional indication (of the reference product) by scientific justification focusing on mechanism of action. • Avoid bridging studies and use same biosimilar product one planned for commercialization. • It is essential to use PD end points (which correlates with efficacy of product) whenever available to find potential difference with reference medicine.


3. Strategies during execution stage of biosimilar development During this stage, resources’ tasks are distributed and teams are informed of responsibilities. This is a good time to bring up important project related information.Below are the key strategies useful during execution stage of Biosimilar development. • Focus on product quality • Accelerate patient accrual by educational program. • Conduct PK studies in homogenous population ( e.g healthy human volunteers can be selected if toxicity is not a cause of concern). 4. Strategies during monitoring & control stage of biosimilar development During this stage, it is important to compare project status and progress to the actual plan and do what is necessary to keep the project on track. Below are the key strategies useful during monitoring and control stage of Biosimilar development. • Use multiple US/EU reference product lots throughout it’s shelf life for establishing acceptable criteria. • GMP requirements like appropriate aseptic technique, stability data, storage, transport, refrigeration is upmost important for the approval. • Strict controls are always in place during manufacturing to ensure that minor differences do not affect the way the medicine works or its safety. • It is essential to control purity of product and technical specification ( control traces of residues from the mfg. process meeting acceptable levels). • Ensure GCP and other regulatory compliance while conducting clinical trial. 5. Strategies during closure/ end of clinical development stage of biosimilar development After project tasks are completed and regulatory has approved the outcome, an evaluation is necessary to highlight project success and/or learn from project history, if required change a process or to solve a problem in order to benefit the organization. Below are the key strategies useful during end of clinical development stage of Biosimilar development.



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• Collect safety information throughout the clinical development including during PK/PD studies.

• Plan to collect spontaneous adverse drug reactions and submit PSURs to the regulatory agency to detect signal.

• Submit post marketing proposal keeping monitoring of Immunogenicity of biological medicine as same is important from regulatory perspective after long term follow ups.

• During commercialization strategies, choose markets with limited or no access to innovator biologic.

• Approval for the additional indication is supported by robust comparative studies and scientific evidence, submit dossier for the same with sound justification. • Develop educational material, patient alert cards and inclusion of patient in registry to manage specific risk.

• Select country/ region where regulatory agencies are willing to work with companies to bring Biosimilar market to reduce healthcare cost. • Prioritize market entry based on changes in regulatory approvability commercial viability.

Figure 3.0: Patent expiry dates on best-selling biological




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Source: Generic and Biosimilar initiatives, http://www.gabionline.net/Biosimilars




Conclusion Market for the Biosimilar is growing in faster pace, many companies are struggling to enter in to market due to unique challenges in Biosimilar development and commercialization. Complex regulatory pathway is the biggest hurdle. It is important to adopt integrated strategic plan at the start of program having opinion from experts and stepwise input on regulatory and market. It is also important to design Biosimilar clinical development plan keeping focus on patient enrolment and appropriate clinical end points.

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8. Pombo ML, Di Fabio JL, Cortés Mde L (2009) Cortes Review of regulation of biological and biotechnological products in Latin American and Caribbean countries, Biologicals, 37 (5): 271-276 . 9. Minghetti P, Rocco P, Cilurzo F, Vecchio LD, Locatelli F,et al (2012) The regulatory framework of biosimilars in theEuropean Union. Drug Discovery Today 17(1-2): 63–70. 10. Kay J (2011) Biosimilars: a regulatory perspective from America. Arthritis Research & Therapy 13(3): 112 11. Rotenstein, LS, Ran N, Shivers JP, Yarchoan M, Close KL, et al (2012) Opportunities and Challenges for Biosimilars.

References

12. Rotenstein, LS, Ran N, Shivers JP, Yarchoan M, Close KL, et al (2012) What’s on the Horizon in the Global Insulin Market? Clinical Diabetes 30(4): 138–150.

1. Guidelines, Biosimilars in the EU, Information guide for healthcare professionals, European medicines agency.

13. Generics and Biosimilars Initative. Biosimilar G-CSF prescribed more than originator (2013) Accessed .

2. Considerations in Demonstrating Interchangeability With a Reference Product Guidance for Industry, U.S. Department of Health and Human Services, Jan 2017.

14. essler M, Goldsmith D, Schellekens H (2006) Immunogenicity of biopharmaceuticals. Nephrology, dialysis,transplantation: official publication of the European Dialysis and Transplant Association – European RenalAssociation 21 Suppl 5: 9–12.

3. Raymond Donninger, Analysis of characterization of biosimilars versus new biologic entities (NBEs), BioPharm International 25(10). 4. Pandya PA (2017) Managing Pharmaceuticals and Life Sciences Projects on a Global Scale: A Project Management Perspective. J Bioanal Biomed 9: 169-172. doi: 10.4172/1948-593X.1000173 5.

Knezevic I, Griffiths E, (2011) Biosimilars — Global issues, national solutions, Biologicals 39(5): 252-255.

6. Gravel P, Naik A, Le Cotonnec J.Y (2012) BiosimilarrhG-CSFs: How similar are they? Target Oncol, 7 pp 3-16 . 7. Prashant Pandya (2017) “Managing Complex R&D Projects- Strategies from Project Management Perspectives”. Chronicles of Pharmaceutical Science 1(3): 113-117.


15. EuropaBio. EuropaBio& Biosimilar Medicines (2008). 16. International Alliance of Patients’ Organizations (2006) Briefing Paper on Biosimilar Medicines. 17. Koren E, Zuckerman L, Mire-Sluis A (2002) Immune Responses to Therapeutic Proteins in Humans – ClinicalSignificance, Assessment and Prediction. Current Pharmaceutical Biotechnology 3(4): 349– 360. 18. Abraham I, MacDonald K (2012) Clinica safety of biosimilar recombinant human erythropoietins. Expert Opinion onDrug Safety 11(5): 819–40 .
