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European Biopharmaceutical Review
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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.
Conclusion
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.
References
1. Hematological cancers drug pipeline update, BioSeeker Group, 2013.
Visit:
www.researchandmarkets.com/reports/1197061/hematological_cancers_drug_pipeline_update_2013
2. Global cancer facts & figures (2), American Cancer Society, 2011.
Visit:
www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-027766.pdf
3. International Myeloma Foundation, Multiple Myeloma. Visit: http://myeloma.org/pdfs/IMF_MMFS.0110.pdf
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:
www.ajpblive.com/media/pdf/AJPB_10nov_Farber_360to370.pdf
5. Bauer S, Romvari E, Treatment of chronic myeloid leukemia following
imatinib resistance, Clinical Journal of Oncology Nursing
13(5):pp523-534, 2008. Visit:
www.ons.org/ClinicalResources/CML/media/ons/docs/clinical/CML/bauer.pdf
6. Healthplus24, Overview of anemia. Visit: www.healthplus24.com/diseases/anemia.aspx
7. World Federation of Hemophilia. Visit:www.wfh.org/en/page.aspx?pid=646
8. Annual Global Survey, World Federation of Hemophilia, 2012. Visit: www1.wfh.org/publications/files/pdf-1488.pdf
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:
www.sciencedirect.com/science/article/pii/S1551714411002539
10. Veliz M, Pinilla-Ibarz J, Treatment of relapsed or refractory
chronic lymphocytic leukemia, Cancer Control 19(1): pp37-53,
2012.Visit:http://moffittcancercenter.com/CCJRoot/v19n1/pdf/37.pdf
11. FDA announces changes in drug center’s oncology office. Visit:
www.fda.gov/newsevents/newsroom/pressannouncements/ucm271501.htm
12. European Medicines Agency, Overarching biosimilar guidelines. Visit:
www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp#Overarchingbiosimilarguidelines
13. Fact sheet: breakthrough therapies. Visit:
www.fda.gov/regulatoryinformation/legislation/federalfooddrugandcosmeticActFDCAc/significantamendmentstotheFDCAct/
FDASIA/ucm329491.htm
14. Pharmacyclics, J&J get FDA shortcut for cancer drug, MSN Money,
2013. Visit:
http://money.msn.com/top-stocks/post.aspx?post=8217134f-98e2-4359-b41c-aa640155969d
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