Biosimilars

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Winning the Biosimilar Race: Trastuzumab Biosimilar Phase III Breast Cancer Study

At a Glance

A sponsor of a global Phase 3 study of a trastuzumab biosimilar came to PSI after falling behind schedule with their current CRO. Drawing on PSI’s biosimilar experience going back to the first such product ever approved by the FDA, we supported the sponsor in recruiting the required 800 patients in just over a year, leading to an EMA approval. Before getting there, though, we had to navigate additional challenges, including an unexpected delay that led to late site activation – just before the summer slow-down.

Phase 3 study in a Trastuzumab biosimilar

Sponsor Challenges

Speed and cost are key for biosimilar development, but development is not necessarily less complex than for a reference biologic. It requires state-of-the-art manufacturing expertise to ensure the biosimilar is “highly similar” with no significant clinical differences in safety profile, efficacy, and potency. Competition for patients against other studies with novel therapeutics often amplifies these challenges.

For PSI’s transition of a global Phase 3 study of a trastuzumab biosimilar in HER2+ early breast cancer patients, it was critical to understand the patient flow from surgery to chemotherapy and back. An additional challenge was that the sponsor’s previous CRO had placed the study primarily in Western countries, where higher standards of care and availability of trastuzumab are common.

How our team made a difference

1) Understanding the landscape

PSI started by thoroughly assessing the country landscape and the product’s reception by sites from our vast oncology network. We selected 100 sites in 10 countries in Eastern Europe, Asia-Pacific, Latin America, and South Africa. The US was also included due to prior expectations from the FDA. The data from other countries was perfectly acceptable.

2) Ready for the green light

Our startup roadmap had to be adjusted when the sponsor put the study on hold for internal reasons, leading to almost half a year of delay in site activation. While waiting for the go-ahead to resume activation, the PSI team prepared contracts ahead of time and had vendors and sites in standby mode. The preparation paid off: as soon as PSI was notified, our teams activated the remaining sites almost simultaneously.

3) Relentless focus on patient enrollment

Because of the delay, site activation occurred just before the summer break, leading to a slow start to patient enrollment. PSI and the sponsor decided to implement several enrollment-boosting measures and organized local investigator meetings for open discussion. A common concern we heard from sites was time and resources, so we optimized site processes to make their work more efficient and focused on the personal relationships of our CRAs and Medical Monitors with investigators and site staff. By optimizing our SDV strategy, close cost control, and the implementation of a blinding system that allowed us to perform drug accountability without the need for a whole unblinded team, we obtained important cost efficiencies.

Program Successes and Outcomes

  • 800 patients enrolled in just over a year
  • Last patient enrolled only 2 months later than initial goal, despite 6-month startup delay
  • Successful FDA inspection and EMA approval

Learn how PSI can support your hemophilia study at the resources below or contact us today

About Us

For 25 years, we have built trusted relationships with biotech sponsors, with 90% of our customers being repeat and referral. 

Oncology Experience

Breast Cancer, Lung Cancer, Prostate Cancer, Colorectal Cancer, Ovarian Cancer, and other Oncology indications. 93 percent of PSI’s oncology studies meet or beat projected enrollment timelines.

The Future of Oncology Clinical Research

This white paper provides essential insights for sponsors into the trends with the greatest potential to affect clinical trial design and operationalization.

Winning the Biosimilar Race: Trastuzumab Biosimilar Phase III Breast Cancer Study Read More »

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Putting the Focus Back on Site Relationships in Clinical Trials

Are Your CRO’s Site Relationships Helping or Harming Your Clinical Trial?

Solid site relationships are the backbone of successful clinical trials. Without happy, supported sites, enrollment simply cannot happen predictably or within budgetary constraints. Yet fostering deep site relationships is often overlooked because many CROs are simply unable or unwilling to put in the effort, resources, and time necessary to do so.

This task has only grown more complex in recent years. While historic challenges like staffing shortages, trial complexity, and issues related to site startup have intensified, they are now joined by the need to often learn and implement unfamiliar new technologies with little support and training.

Download our new white paper to learn about:

  • Top site challenges and how sponsors can help mitigate site burdens
  • How PSI’s experienced team navigates and strengthens site relationships
  • How strengthening site relationships helped one sponsor get their enrollment back on track

About Us

For 25 years, we have built trusted relationships with biotech sponsors, with 90% of our customers being repeat and referral. 

Case Study

A sponsor of a pivotal Phase 3 prostate cancer study investigating a radiopharm product approached PSI for support based on our experience and established network of 300 global radiopharmaceutical sites. 

Global Reach

Clinical trial sponsors working in oncology, hematology, IBD, infectious diseases, multiple sclerosis, and many rare diseases rely on PSI’s guidance and experience. 

Putting the Focus Back on Site Relationships in Clinical Trials Read More »

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7 Challenges for Sponsors of Biosimilar Clinical Trials

This is the second of two articles based on our new white paper on biosimilar development in Inflammatory Bowel Diseases (IBD). In our previous article, we discussed some of the common regulatory considerations for biosimilar clinical trials. In this article, we focus on some of the greatest design and operational challenges. In the highly competitive IBD landscape, understanding the unique obstacles that biosimilar development can pose can help sponsors predict potential challenges and pivot effectively.

Designing biosimilar clinical trials to support comparability and future extrapolation requires careful planning from the outset to ensure these and other criteria are met. Sponsors should consider working with a partner experienced in understanding and overcoming the challenges of these studies. Key challenges include:

  • Endpoint selection: Ulcerative colitis, Crohn’s disease, and other IBDs are multifactorial diseases with highly subjective manifestations. When determining endpoints for biosimilar trials in IBD, it is important to select endpoints that capture relevant aspects of the disease and are sensitive enough to provide clinically meaningful results.
  • Ethical considerations: Sponsors must balance the need for clinical research with the wide availability of effective treatments for IBD. Convincing patients with established treatment regimens to participate in a biosimilar clinical trial often requires providing supporting educational materials and clear messaging to ensure informed consent.
  • Study design: Availability of existing treatments also impacts study design considerations such as blinding and the use of placebo. In cases where administration routes of the biosimilar and reference biologic vary, maintaining blinding may be challenging or impossible.1 The long half-lives of many biologics can also impact the determination of an appropriate washout period for patients who have been previously treated with the reference medicine.
  • Variability: Microheterogeneity is a common characteristic of all biologic drugs.2 Sponsors must have plans for controlling variability of manufacturing processes and raw materials to ensure that the biosimilar’s product quality remains within an acceptable range, particularly as the proprietary technology used to develop the original molecule will be unknown.3 An iterative process is therefore necessary to “guide” the fingerprint of the biosimilar towards that of the original medicine.4
  • Long-term safety: Due to the shorter length of biosimilar trials compared to the real-world treatment duration of IBD, there is a need for long-term safety and immunogenicity data. Assessing long-term safety requires resource allocation and planning for additional studies or post-marketing surveillance.
  • Patient bias: The “nocebo effect” is a negative effect of a pharmacological or non-pharmacological medical treatment induced by patients’ expectations and unrelated to the physiological action of the treatment.”5 Several studies investigating a switch to IFX biosimilar have reported higher discontinuation rates in transitioned patients than in patients continuing treatment with IFX, and it has been suggested that may be influenced by a negative perception of biosimilars.6,7,8
  • Lack of clinical and scientific interest: Investigators may be hesitant to participate in clinical trials with biosimilars compared to studies involving new biological molecules or novel pathways. Such clinical trials may be of little interest to patients who already have access to the reference product as part of the standard of care. This has led to a trend towards conducting trials in countries where the reference drug is unavailable or not covered by insurance plans.

Success starts with the right partner

Designing effective IBD trials requires careful planning from the outset to ensure these and other criteria are met. Sponsors should consider working with a partner experienced in understanding and overcoming the challenges of these studies. Sponsors that understand the unique challenges that come with IBD development can set themselves up for success.

With the help of PSI’s VISIONAL™, challenges with IBD patient enrollment and site selection can be predicted and mitigating, allowing sponsors to pivot quickly saving valuable time and money. With a network of more than 3,900 global IBD sites, and an expert team, PSI specializes in delivering pivotal Phase 2 and 3 IBD trials. Download the full white paper here, or contact us to learn more.

1 Lai ZV, La Noce A. Key design considerations on comparative clinical efficacy studies for biosimilars: adalimumab as an example. RMD Open. Published online February 1, 2016. doi:10.1136/rmdopen-2015-000154

2 Schiestl M, Stangler T, Torella C, Cepeljnik T, Toll H, Grau R. Acceptable changes in quality attributes of glycosylated biopharmaceuticals. Nat Biotechnol. 2011;29(4):310-312. doi:10.1038/nbt.1839

3 Caldwell B. Variability of Biologics and its Impact on Biosimilar Development. European Medical Journal. Published online September 12, 2019:22-30. doi:10.33590/emj/10312818

4 Vulto AG, Jaquez OA. The process defines the product: what really matters in biosimilar design and production?. Rheumatology (Oxford). 2017;56(suppl_4):iv14-iv29. doi:10.1093/rheumatology/kex278

5 Pouillon L, Socha M, Demoré B, et al. The nocebo effect: a clinical challenge in the era of biosimilars. Expert Review of Clinical Immunology. 2018;14(9):739-749. doi:10.1080/1744666x.2018.1512406

6 Bressler B. Is there an optimal sequence of biologic therapies for inflammatory bowel disease?. Therap Adv Gastroenterol. 2023;16:17562848231159452. Published 2023 Apr 5. doi:10.1177/17562848231159452

7 Bernard EJ, Fedorak RN, Jairath V. Systematic Review: Non-medical Switching of Infliximab to CT-P13 in Inflammatory Bowel Disease. Dig Dis Sci. 2020;65(8):2354-2372. doi:10.1007/s10620-019-06036-0

8Scherlinger M, Germain V, Labadie C, et al. Switching from originator infliximab to biosimilar CT-P13 in real-life: The weight of patient acceptance. Joint Bone Spine. 2018;85(5):561-567. doi:10.1016/j.jbspin.2017.10.003

About Us

For 25 years, we have built trusted relationships with biotech sponsors, with 90% of our customers being repeat and referral. 

GI Experience

We match theory to practice, making sure that our teams know what’s going on right now with IBD around the globe.

Demystifying Biosimilar Development Regulations

As these drugs continue to grow in popularity with physicians and patients alike, it is crucial for sponsors to understand what these changes mean for current and future IBD development activity. 

7 Challenges for Sponsors of Biosimilar Clinical Trials Read More »

blurred female scientist using a dropper and test tube

Demystifying Biosimilar Development Regulations: Key Considerations for Sponsors

Biosimilars – biological medicines highly similar to another already approved biologic – have emerged in recent years as an area of rapid development activity, especially for Inflammatory bowel diseases (IBD) such as Crohn’s disease (CD) and ulcerative colitis (UC). While these drugs have historically faced the common misconception that they are less safe and less effective compared to the original biologic product, biosimilars undergo very rigorous and extensive testing before receiving regulatory approval, and public perceptions are starting to shift. As these drugs continue to grow in popularity with physicians and patients alike, it is crucial for sponsors to understand what these changes mean for current and future IBD development activity.

In our new white paper, Similar But Different: Regulatory and Operational Considerations for Biosimilar Clinical Development in IBD, we discuss how biosimilars have transformed the treatment landscape for IBD in the past decade, their current therapeutic uses in CD and UC, and global regulatory considerations for running biosimilar clinical trials in IBD. This post reviews some of the regulatory factors that are evaluated for biosimilar medications during the course of a trial. The list of full regulatory requirements varies by country; however, these factors are common parts of the evaluation process by many regulatory bodies.

Comparability

Even licensed biologics undergo changes in relevant molecular attributes over time.1 In a study of biologics licensed for use in rheumatology, all reported changes to the production process over time, including change of cell culture supplier and modification of the protein purification procedure.2 The original medicines available today are therefore not identical but comparable to those available in previous years. 

Biosimilars must demonstrate clinical comparability with the reference drug (the original biologic) in order to receive regulatory approval. The following table outlines the properties and methods used to demonstrate comparability in a biosimilar for infliximab (IFX).3,4

Properties How was similarity determined? 
Protein structure and production quality  Detailed laboratory analysis of the structural characteristics of different batches of the drug 
Pharmacokinetic, pharmacodynamic and toxicological tests on animals  "In vitro" and "in vivo" tests on different species 
Pharmacokinetic, pharmacodynamic and toxicological tests on humans  Initial clinical trials 
Clinical efficacy and safety  Major clinical trials
Safety in everyday practice  Risk management plan , Post-marketing trials (Phase 4),  Routine reporting of side effects,  Pharmacovigilance 

Extrapolation

The initial comparability tests are conducted in the indication and population that are considered the most sensitive to detect clinically significant differences in safety, immunogenicity, and efficacy between the original and biosimilar drug. If the biosimilar product is highly similar to the reference medicine and has comparable safety and efficacy in this therapeutic indication, safety and efficacy data may then be extrapolated to indications already approved for the reference medicine.5

Extrapolation must be supported by all the scientific evidence generated in other comparability studies. In these cases, clinical trials are often not required to be repeated for all indications; instead, changes are approved based on data from quality and in vitro comparability studies. The possibility of extrapolation is dependent on the regulatory landscape of the particular country or countries in which the clinical trial is being conducted. In the EU, which pioneered biosimilar regulation by establishing a solid framework for approval, decisions based on extrapolation are dependent on a number of criteria:5,6

  • Mechanism of action: The mechanism of action of the active substance should be mediated by the same receptor in both the initial and extrapolated indication. If the mode of action is complex, involving multiple receptors or building sites, additional studies may be needed to prove that the biosimilar and reference medication will behave similarly.
  • Study population: Comprehensive comparability studies must demonstrate that the biosimilar is highly similar to the reference medicine in a “key population” in which potential differences can be detected.
  • Clinical setting: Data from one indication may not be directly applicable to an indication within another therapeutic area where the mode of action, posology, or pharmacokinetics may be different. Additional studies may be needed in this case.
  • Safety data: A comparable safety profile for the proposed indication must be established in one therapeutic indication before extrapolation. Comparability must be shown at the structural, functional, pharmacokinetic, and pharmacodynamic levels, and efficacy must be comparable.
  • Immunogenicity data: Extrapolation of immunogenicity data always requires justification as immunogenicity is determined by more than product-related characteristics. Factors relating to patient (age, immune status), disease (comorbidities, concomitant treatments) and treatment-related factors (route of administration, length of exposure) must be considered.

Meet the challenges of your IBD trial with confidence

Understanding each country’s regulatory intricacies of biosimilar development is crucial for the success of your trial. With a network of more than 3,900 global IBD sites, and a regulatory team with local regulation expertise, PSI specializes in delivering studies on time and with quality data.

Discover the full white paper here, or contact us to learn more about running your pivotal Phase 2 and 3 IBD trials with PSI.

1 Schiestl M, Stangler T, Torella C, Cepeljnik T, Toll H, Grau R. Acceptable changes in quality attributes of glycosylated biopharmaceuticals. Nat Biotechnol. 2011;29(4):310-312. doi:10.1038/nbt.1839. https://www.ema.europa.eu/en/human-regulatory/overview/biosimilar-medicines-overview

2 Schneider C. Biosimilars in rheumatology: the wind of change. Annals of the Rheumatic Diseases. 2013;72(3):315-318. doi:10.1136/annrheumdis-2012-202941

3 European Medicines Agency. Assessment report Inflectra. European Medicines Agency. June 27, 2013. https://www.ema.europa.eu/en/documents/assessment-report/inflectra-epar-public-assessment-report_en.pdf

4 Krznarić Ž. Biosimilars in Inflammatory Bowel Disease: From Theory to Practice. Presented at: PSI Internal Training; June 27, 2023.

5 European Medicines Agency, European Commission. Biosimilars in the EU – Information Guide for Healthcare Professionals. European Medicines Agency. 2019. https://www.ema.europa.eu/en/documents/leaflet/biosimilars-eu-information-guide-healthcare-professionals_en.pdf.

6 European Medicines Agency. Biosimilar Medicines: Overview. European Medicines Agency. April 26, 2023. Accessed July 3, 2023. https://www.ema.europa.eu/en/human-regulatory/overview/biosimilar-medicines-overview.

Demystifying Biosimilar Development Regulations: Key Considerations for Sponsors Read More »

pair of gloved hands drawing up medicine from a vial with a needle

Similar But Different: Regulatory and Operational Considerations for Biosimilar Clinical Development in IBD  

The rise of IBD biosimilars and what comes next

Biosimilars present untapped potential for expanding patient access and improving treatment options in Inflammatory Bowel Disease (IBD) and other therapeutic areas, but these trials also bring unique challenges and regulatory considerations.

In this white paper, you’ll learn how biosimilars have transformed the treatment landscape for IBD in the past decade, their current therapeutic uses in Crohn’s disease and ulcerative colitis, and global regulatory considerations for running biosimilar clinical trials in IBD.

Download our new white paper to learn about:

  • IBD epidemiology and current biosimilar treatment methods
  • Regulatory considerations and other challenges for biosimilar trials
  • Future opportunities for biosimilar therapeutics

Similar But Different: Regulatory and Operational Considerations for Biosimilar Clinical Development in IBD   Read More »

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