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European Biopharmaceutical Review

A Complex Puzzle

On the surface, haematology and oncology may appear to be one large field, however it is made up of smaller mosaics that could be the difference between the failure and success of biologic products

Biological drug development focuses heavily on speciality products for diseases with a high global unmet need, where researchers target smaller patient populations and fewer patients per site. One area where this approach is evident is the haematology and oncology field, a drug class that encompasses a wide spectrum of rare and complex blood disorders and blood-related cancers.

Today, clinical trials have advanced beyond simply identifying active drugs and evaluating general treatment response. Targeted therapy models and varying classifications determining which biologics should fall under certain regulatory pathways can cause confusion which is further muddled by differing global regulations for biologics.

Discovering Solutions
These changing dynamics pose challenges for biopharmaceutical companies and contract research organisations (CROs). With clinical trials frequently targeting rare diseases, there are difficulties in executing patient recruitment, investigational design, and data capture.

The need for tailor-made approaches focused on the understanding of the specific peculiarities of haematology and oncology conditions, as well as the treatment community addressing them, is critical. To be successful, such approaches require early planning, feasibility, strict attention to detail, and clinical teams versed in handling not just the therapeutic challenges along the development continuum, but the unique operational issues. Several key operational issues should be addressed when managing biologics trials. Among them are challenges in patient enrolment and important regulatory considerations.

Need Spurs Activity
Medicines targeting malignancies such as leukaemia, lymphoma, myeloma, myelodysplastic syndromes and myeloproliferative diseases make up the majority of haematology and oncology drugs in the pipeline. The class includes ‘supportive care’ drugs, used for several diseases and agents for non-malignant indications such as haemophilia, anaemia and thrombocytopenia.

Despite treatment advances, unmet needs remain high. There are a reported 392 companies, plus their partners, developing 625 haematological cancer drugs in 1,237 developmental projects in oncology (1). Haematologic cancers represent the fifth most commonly occurring cancers and the second-leading cause of cancer death. In leukaemia cases, which include chronic and acute myeloid leukaemia (CML, AML) and chronic and acute lymphocytic leukaemia (CLL, ALL), an estimated 350,000 people worldwide are diagnosed each year, with about 257,000 deaths annually. Non-Hodgkin’s lymphoma (NHL) is the seventh most frequently occurring cancer, and multiple myeloma affects an estimated 750,000 people (2,3).

Tackling Obstacles
Treatment approaches for haematologic cancer include chemotherapy, targeted drugs, biologics, immunotherapy, and blood stem cell transplant. This area has seen stories of almost incredible success, such as the development of rituximab, the most widely used therapeutic monoclonal antibody, and imatinib, the first drug engineered to attack the molecular mechanism of neoplastic disease.

The use of rituximab has been established for the treatment of B-cell-derived haematologic malignancies, including follicular lymphoma and diffuse large B-cell lymphoma, the two most commonly occurring subtypes of NHL and CLL (4). Imatinib, a first-generation tyrosine kinase inhibitor, is the initial treatment of choice in CML. Imatinib specifically targets the abnormal protein BCR-ABL, which triggers the onset of CML. Resistance to the drug, however, has limited its long-term efficacy. Thus, effective second-line therapies for CML continue to be sought (5). Similarly, new drug approaches are needed in treating aggressive NHL, where standard care therapy achieves long-term remission in less than half of cases.

In non-malignant haematology, anaemia is known to affect millions of people and is one of the most prevalent public health concerns in many developing countries (6). Incidence of haemophilia, an inherited bleeding disorder, is rarer, with about one in 10,000 people born with the disease (7). A global survey by the World Federation of Hemophilia identified 167,110 people with the condition in 108 countries (8).

Complex Trial Designs
As demand for improved and alternative biological treatments increases, so have the efforts to carry out more innovative clinical trials. For example, clinical trials in haemophilia typically involve combinedphase studies that may start with a firstin- human dosing for a single-dose Phase 1 or pharmacokinetic (PK) trial, followed by a multiple-dose Phase 2 or 3 study evaluating efficacy and safety. This design allows for accurate detection of low plasma levels of the test drug, which is necessary for determining the terminal half-life of the product – something that would not be possible in normal subjects who produce such protein.

The experience with this class of drugs also allows for well-established risk management strategies, in which studies are initially performed in populations at lesser risk of developing adverse events – for example, patients previously exposed to agents with a lesser known risk of developing neutralising antibodies. Safety reviews conducted by independent data and safety monitoring boards are pre-planned at appropriate points, and determinations of pre-specified safety levels enable continuation of the trial and initiation of subsequent studies. Using such trial designs allows for the staggered start of required studies and results in a more efficient development pathway. They can also potentially usher in improved products to the market by providing longterm follow-up data in a feasible timeframe.

The use of adaptive designs to evaluate new cancer therapies, while considered more efficient statistically, is not yet widespread. Researchers find that this is due to the complex and computationally intensive methods needed, the substantial effort for planning the trials, and a need for regulatory guidance in many indications (9).

Patient Recruitment
The ability to shed traditional models in patient recruitment is another critical consideration when conducting biologic development. The focus of research for rare diseases has shifted to special subpopulations of patients at higher risk: the recent Phase 3 trial of imatinib for Philadelphia chromosome (positive CML), for example, would target most newly diagnosed patients with the condition. Mid-sized haematology sites would then recruit an average of five to ten patients in a reasonable timeframe.

Today, as the focus has turned into the poorer-response subgroups, the recruitment approach is vastly different. For instance, in CLL, researchers are testing patients for the presence of the chromosome 17p deletion, a subpopulation of the disease that has poorer prognosis and where improved therapies are greatly needed, comprising five to eight per cent of patients with CLL (10). Even large clinical sites may see just one of these patients in a year. Trials with such long inactivity periods require a different management in order to keep the sites prepared and trained, and avoid demotivation and potential quality issues due to lack of familiarity with the procedures.

Furthermore, targeting patients with rapid disease progression further challenges recruitment efforts because certain patients may only meet a trial’s inclusion or exclusion criteria for a short period of time. In these cases, effective management of patient accrual is critical and requires a thorough understanding of patient-screening flows at clinics. Overlooking seemingly tiny details could result in significant deficiencies in study performance. Strong expertise around the logistics of diagnostic tests for subpopulations in haematology and oncology trials is also important. Teams must recognise that such testing may not be usual practice before a treatment option is available and, therefore, tissue samples may not have been preserved for analysis.

Extensive logistical planning is also required in the recruitment for rare disease trials. To improve enrolment performance, sponsors need to engage principal investigators as early as possible in the planning phase. This enables relationships to be built from the outset, particularly in terms of conducting initial feasibility and initial on-site visits. Involving patient advocacy groups and addressing potential treatment-access issues is also essential, but following the conventional recruitment path of combing external databases, selecting a site, and then conducting the qualifications after study rollout is not reliable in these cases.

Regulatory Considerations
Adeptly handling relationships with regulatory authorities, research ethics committees and institutional review boards (IRBs) is crucial in haematology and oncology drug development. Sites and investigators should be well-versed in local regulations governing biological product development and clearly understand how those requirements influence clinical programmes for peculiar indications.

With trials in rare disorders usually spanning multiple countries across the globe, IRBs and some regulatory bodies with limited exposure to these diseases might question a study’s merit or ethics. Therefore, it is crucial that the submission of investigational plans in haematology and oncology and further interaction regarding trial approvals is handled by specialised teams. This will ensure an informed dialogue between regulators and the appropriate medical experts. Aiding such efforts in US trials was the decision by the Food and Drug Administration (FDA) in late 2011 to reorganise its Center for Drug Evaluation and Research’s (CDER) Office of Oncology Drug Products and rename it as the Office of Haematology and Oncology Products (OHOP). The agency said it made the move to create greater clarity and more transparent interactions with sponsors about the requirements in bringing cancer treatments to the market (11).

The emergence of the biosimilars – or follow-on biologics – market has added a further layer of complexity to regulatory considerations in haematology and oncology. The FDA released draft guidance on biosimilar development early last year and regulations have been in place in Europe since 2006 (12). Biosimilar products have become more common in haematology and oncology, including several granulocyte colony stimulating factors (G-CSFs) approved in Europe. G-CSFs stimulate the production of white blood cells. A recombinant form of G-CSF is used with certain cancer patients to accelerate recovery from neutropenia after chemotherapy, allowing higher-intensity treatment regimens.

Demonstrating comparable efficacy and safety for a follow-on biologic will, in many cases, require human trials of similar size to those for the innovator product. When conducting biosimilar programmes in haematology and oncology, the understanding of patient dynamics and drivers during enrolment is integral. For example, in trials evaluating biosimilars of anti-CD20 monoclonal antibodies, such as rituximab for NHL, it is important to recognise that patients indicated to receive the product may have access to the innovator drug and, thus, have little interest in enduring the additional procedures and potential risks of a clinical trial for no expected gain. Additionally, there are many ethical and practical issues that complicate the possibility of running biosimilar clinical studies in places where patients may lack adequate access to modern treatment.

‘Breakthrough’ Benefit
Expedited drug approval pathways in Europe and the US have been in place for several years, designed to accelerate the development and review of drugs to treat serious and life-threatening diseases where there are few available options. A new pathway known as ‘breakthrough therapy,’ created by the FDA in 2012, could end up benefiting rare-disease efforts in malignant and non-malignant haematology the most (13).

Unlike other expedited pathways, which apply to conditions void of adequate treatment, products that are granted the breakthrough designation are thought to provide significant improvements over existing drugs based on substantial promise shown in early trials. Ibrutinib, a targeted agent for the rare blood cancers mantle cell lymphoma and Waldenstrom’s macroglobulinemia, was awarded the breakthrough classification earlier this year. The designation could allow the FDA to approve the drug in those indications after just one expanded early-stage study (14). Ibrutinib’s development programme targets real-world patients who possess genetic mutations that predispose them to poorer therapy outcomes. The belief is that these types of studies, based on molecularly defined subsets, will aid in selecting candidates for breakthrough designation.

On the surface, haematology and oncology may appear as a large field by sheer pipeline volume and market growth standards. However,in reality this space is defined more as a mosaic of many small fields, each of them dominated by their specific peculiarities. Today, with biologics studies in haematology and oncology targeting fewer patients per site, and the regulatory climate for these products constantly evolving, being aware of and understanding those peculiarities can spell the difference between project success and failure.


1. Hematological cancers drug pipeline update, BioSeeker Group, 2013. Visit:

2. Global cancer facts & figures (2), American Cancer Society, 2011. Visit:

3. International Myeloma Foundation, Multiple Myeloma. Visit:

4. Farber CM, Axelrod RC, Value of Rituximab for the treatment of hematologic malignancies, The American Journal of Pharmacy Benefits 2(6): pp361-370, 2011. Visit:

5. Bauer S, Romvari E, Treatment of chronic myeloid leukemia following imatinib resistance, Clinical Journal of Oncology Nursing 13(5):pp523-534, 2008. Visit:

6. Healthplus24, Overview of anemia. Visit:

7. World Federation of Hemophilia.

8. Annual Global Survey, World Federation of Hemophilia, 2012. Visit:

9. Lopez MF, Dupuy JF, Gonzalez CV, Effectiveness of adaptive designs for phase II cancer trials, Contemporary Clinical Trials 33(1):pp223-227, 2012. Visit:

10. Veliz M, Pinilla-Ibarz J, Treatment of relapsed or refractory chronic lymphocytic leukemia, Cancer Control 19(1): pp37-53, 2012.Visit:

11. FDA announces changes in drug center’s oncology office. Visit:

12. European Medicines Agency, Overarching biosimilar guidelines. Visit:

13. Fact sheet: breakthrough therapies. Visit: FDASIA/ucm329491.htm

14. Pharmacyclics, J&J get FDA shortcut for cancer drug, MSN Money, 2013. Visit:

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Daniel Mazzolenis is Medical Director, Global Oncology at INC Research, where he is responsible for therapeutic support to non-malignant haematology projects across the company. He has gained an MD, a post-graduate degree in Clinical Pharmacology, and an MBA. A haematologist, his main subject was thrombosis/haemostasis. He has 18 years of experience within the pharmaceutical and CRO industry and is an active member of the DIA and the Argentine Society of Pharmaceutical Medicine.

Swapnil Pandey is Director of Clinical Operations, Global Oncology-Haematology at INC Research, where he oversees global project management and clinical operations for non-malignant haematology projects across the company. He earned his first master’s degree majoring in Applied Industrial Statistics, followed by a second in Clinical Research and Drug Development from the University of Cincinnati. His operational experience spans from early phase, first-in-human studies to large global trials based on complicated multi-phase protocol designs.

Daniel Mazzolenis
Swapnil Pandey
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