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Revista CENIC. Ciencias Químicas
ISSN: 1015-8553
[email protected]
Centro Nacional de Investigaciones
Científicas
Cuba
Ferreira Gaspar Amaral, Luciene; Ferreira Soares, Thaís Talita; Pimenta Suárez, Thaís
Cristina
Technology mapping: Leukemia Treatment
Revista CENIC. Ciencias Químicas, vol. 46, 2015, pp. 206-212
Centro Nacional de Investigaciones Científicas
La Habana, Cuba
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Revista CENIC Ciencias Químicas, Vol. 46, Número Especial, pp. 206-212, 2015.
Technology mapping: Leukemia Treatment
Luciene Ferreira Gaspar Amaral, Thaís Talita Ferreira Soares* Thaís Cristina Pimenta
Suárez**
Senior Specialist in Industrial Property National Institute of Industrial Property *Master Degree in
Intellectual Property and Innovation**Master Degree Student in Intellectual Property and
InnovationTechnical Analist Patents Soerensen Garcia Advogados Associados [email protected]
Recibido: 10 de octubre de 2015.
Aceptado: 4 de noviembre de 2015.
RESUMEN. The increase in the incidence of various cancers has been one of the biggest challenges in the global
public health for decades. Leukemia is a type of cancer that only in 2008 has affected 351,000 people of the world
population. In Brazil, the full treatment is offered by the SHS (Sistema Único De Saúde, in Portuguese) by Cancer
Network, and due to the high cost of therapy, it is urgent to carry out studies that support public policies on access to
medicines. The technology mapping has emerged as satisfactory source of information able to direct the decisions of
policymakers. This study aims at mapping of new technologies for the treatment of leukemia. They will be held a
survey in specialized databases in order to map out new technologies in several stages of clinical trials, and identify
the feasibility of absorption of such technologies by public laboratories through the crossing of information with data
available in patent documents bases. Initially, we identified 1,348 clinical trials involving 770 interventions with
drugs, with 113 products launched and 56 drugs in phase I, II and III, which will have their cross data to the
information available in patent databases. Technological mapping studies provide key information about what are the
advantages and risks of adopting certain technology. The information technology should at least be the basis for the
planning of public access to medicines policies, especially when they are expensive.
ABSTRACT. The generation and management of knowledge is central to the development of new technologies and
products especially those related to emerging technologies. The success of the R + D + i in the specific case of
nanotechnology will be closely linked to the integration of knowledge generated in the different stages during the life
cycle of the R + D + i. This paper aims to analyze influence of knowledge generated from the information contained
in patent documents in an R & D related to carbon nanoonions. To achieve the objective, the Methodology for the
Generation and Knowledge Management (MGGC) it was used as a source of information and are mainly used the
information contained in patent documents, which was processed for later viewing and analysis. The results obtained
show the positive impact of the socialization of knowledge generated.
INTRODUCTION
The increasing attention devoted by the Brazilian government for the best understanding and control of neglected and
re-emerging diseases, involving various work areas in a coordinated action of the executive branch, reveals that in a
future next, new strategies being promoted culminate in lower incidence and to eradicate these ills. On the other hand,
the increasing improvement of health of our population has been accompanied by an increase in the diagnosis of
diseases typically addressed to developed countries, such as cancer (1).
The increase in the incidence of various cancers has for decades been one of the major challenges within the World
Public Health. The multifactorial nature of these diseases, associated with the still little understanding of its
pathophysiology, generate a scenario in which the therapeutic approaches are in constant renewal and review. This
commitment, which is infinitely more robust in developed countries and massively executed by large pharmaceutical
industries, resulting in higher value-added products. Thus, it is imperious streamlining the protocols and drugdispensing processes by Ministry of Health (1).
Leukemia is a type of cancer that affects the hematopoietic tissue cells when not hairy, and in 2008 alone, 351,000
befell the world's population. Subtypes most common are those which affect the formation of bone marrow cell
precursors cells or type B lymphocytes (2), which can be classified as acute or Chronic according to the intensity of the
disease process. Although lower incidence, there are still hairy cell leukemia and chronic myelocytic leukemia (3).
In Brazil, the full treatment is offered by the SUS (NHS, in English) through the Cancer Network, and due the high
cost of therapy, it is urgent to carry out studies that support policies Public access to medicines. Based on a bold
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innovation policy for the productive development aimed at technological development in various sectors industrial in
the country including a special look facing the health sector, was launched in 2007 and thickened the Greater Brazil
Plan in 2011, a partnership building program public-private in order to boost Brazil in a competitive industry the most
several segments of the production chain of the health sector, such as active ingredients and medicinal products for
human use; chemical intermediates and plant extracts for the purpose therapeutic; medical equipment; blood products;
materials, reagents and devices for diagnostics; immunobiologicals; besides providing technical and scientific
development in strategic areas in order to reduce the vulnerability of the National Health System (4).
Partnerships for Productive Development (PDP) are institutional arrangements promoted by the Ministry of Health
whose guidelines for its establishment as a Ordinance No. 837 of April 18, 2012, are access to priority technologies,
rationalization and reduction of strategic product pricing for the NHS and the internalization and development new
high technological density technologies that could induce innovation. These guidelines would be achieved through
partnerships between public and private laboratories preferably with output based on the country so that they would
boost the competitiveness of the domestic industry to maintain balance in the internal market products for health and
the integrity of supply chains (5).
Thus, the mapping technologies have collaborated satisfactory source information capable of directing the decisions
of policymakers. This work aims at mapping new technologies for the treatment of leukemia.
METHODOLOGY
The studies aimed at identifying new technologies present peculiarities inherent to each disease. Thus, there is a
classic methodology to be followed, and it is imperative that existing methods are appropriate to each case (6). This
form, fit within this work, the adaptation of a procedure that would meet determinations to obtain information that
was relevant to that could achieve the goal initially proposed. Thus, with the assistance of Thomson base Reuters
Integrity identified whether the drugs that are being tested for treatment leukemias, as well as the stages of
technological development which are each identified product. In parallel, we performed a crawl in the database
Clinical Trials organized to review and update the literature on the treatment of leukemia. In a third step, the product
of interest was identified to the Ministry of Health and retrieved technological information in document patents to
determine the legal and market issues raised concerning patents. The PatentScope bases of the World Intellectual
Property Organization of Espacenet European Patent Office and the Brazilian Industrial Property Office (INPI). They
were used to deepen the technological information relating to technologies found in the literature. Finally, we
analyzed the development of partnerships production signed by the Ministry of Health of Brazil, among which were
identified drugs, which although originally present another indication comes they are tested and are presented as
promising in the treatment of leukemia according to the diagnosis made.
RESULTS AND DISCUSSION
They were initially identified on the basis Clinical Trials 1,348 clinical trials, 770 interventions involving
medicaments for the treatment of leukemia. In parallel, the search conducted on Integrity base showed launched 97
products and 412 drugs in different phases of clinical development, which will have their data crossed to the
information available in patent databases. The results are and arranged skilled in Figures 1 and 2 below.
Fig. 1: Clinical phase’s drugs for leukemia distribution. Source: Thomson Reuters Integrity (7).
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Based on the analysis of the data presented in Figures 1 and 2, it was observed that 50% of drugs that are still in
development are in the early stages of research, i.e., to mature technologies. These are technologies that are still in
phase clinic accreditation, and therefore require further research. Unless the title clinical research, these technologies
are not paramount interest to making decision, given the urgency of pharmaceutical care. To this end, we highlight at
least those found in Phase III development since this stage technology as well as mature, it has a significant amount
of clinical trials and potential candidate is market, and therefore the object subject to transfer technology.
Fig. 2: Kinds of leukemia distribution. Source: Thomson Reuters Integrity (7).
A careful analysis of the data indicates that studies have focused on the following types of leukemia: acute
myelogenous, chronic lymphocytic, acute lymphocytic and chronic myeloid, respectively, which represent 71% of
total research. In fact, these types of leukemia are the highest worldwide incidence, and as such, turn out to be the
most investment by large pharmaceutical companies.
In Brazil, where the health system both within the municipality and the State as Federal government has a
constitutional obligation to bear the costs of treatment, and foster local production through cooperation agreements,
using partnerships public-private - or Partnerships for Productive Development - it is necessary list some of the
technologies available for immediate pharmaceutical care, with sake of rationalization of government spending.
According to the Brazilian Ministry of Health of the Government, are considered interest for the treatment of some
cancers of the following medicines: mesylate imatinib, bevacizumab, L-asparaginase, rituximab, sirolimus and
everolimus. All these already found in projects of public-private partnerships for local production; however, the set of
oncological technologies being internalized by the companies of the country, priori, some of them are not specifically
identified for treatment of leukemia, but to other therapeutic groups (8). This is justified because 4 (Four) of these
drugs are still under development and study Clinical therapeutic moiety to leukemia as evidenced by Tables 1 and 2:
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Table 1. Drug interest according to the Productive Development Policy (PDP). Source: Thomson Reuters Integrity (7).
DRUG
ORGANIZATION
IMANTINIB
MESYLATE
Novartis
IMANTINIB
MESYLATE
National Cancer Institute
(NCI)
FORMULATION
100 mg – 60 com
40omg – 30 cpm
BEVACIZUMA M.D. Anderson Cancer 100 mg/ 4 ml
B
Center
400 mg/16ml
LASPARIGINAS
E
LASPARIGINAS
E
LASPARIGINAS
E
LASPARIGINAS
E
RITUXIMAB
PHASE
LEUKEMIA
- FIRST
CONDITION
LAUNCHED
2006
-
2001
II
Câncer Breast,
ovary, kidney, 2004
lung, colorectal
III
Orphan Europe
III
10.000 UI
ERYtech
II
Orphan Europe
II
Roche
2001
II
ERYtech
100 mg/10 ml
500 mg/100 ml
CML
ALL
GIST
LAUNCHED
FIRST
TIME
LAUNCHED
2009
III
LEUKEMIA
ACUTE
LYMPHOCYTI
C
III
III
III
Non-Hodgkin
- lymphoma and
1997
follicular
lymphoma
Jefferson 1 mg
II
Imunossupressor 1999
2 mg
2,5 mg
Breast
cancer,
EVEROLIMUS Novartis
5 mg
I
renal carcinoma, 2004
10 mg
stroma
Legend: CML – chronic myelogenous leukemia; ALL - acute lymphoblastic leukemia; GIST - gastrointestinal
stromal tumors
SIROLIMUS
Thomas
University
Table 2 below shows the clinical studies conducted for each drug of interest to the Ministry of Health of Brazil.
Considering that more studies Clinicians are available, the greater the maturity of the technology in question, it
confirms that, to analyze the interventions with drugs listed by the PDP, believed that the Ministry of Health could
consider the possibility of inserting at least the rituximab pharmaceutical protocol for leukemia, since the same out
previously listed for use in rheumatic disorders. Since the technology, being internalized regard to the first launch of
the product, which can result in new patents for the treatment of leukemia that are not part of the original agreement
technology transfer. Therefore, it is urgent lifting of patents related to products already launched in the market and are
now being redirected for the treatment of leukemia in order to support new development agreements technological or
redirection of partnerships already established.
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Table 2. Clinical studies - Drug interest under the Productive Development Policy (PDP). Source: Clinical Trials (9).
DRUG
A
B
C
D
E
F
G
H
I
J
L
TOTAL
IMANTINIB MESYLATE
3
1
11
2
49
66
139
34
2
1
4
312
9
2
1
13
3
2
163
BEVACIZUMAB
1
L-ASPARIGINASE
1
RITUXIMAB
1
2
36
48
62
8
9
90
89
110
30
3
12
344
24
25
24
9
1
2
85
24
23
24
9
1
2
85
SIROLIMUS
EVEROLIMUS
2
1
TOTAL
4
2
24
2
224
251
368
92
3 9 23
1002
A- NO LONGER AVAILABLE; B – AVAILABLE; C - NOT YET RECRUITING; D - ENROLLING BY
INVITATION; E - ACTIVE, NOT RECRUITING; F – RECRUITING; G – COMPLETED; H – TERMINATED; I APPROVED FOR MARKET; J – SUPSENDED; L – WITHDRAWN
Information Technology
The following are arranged technological information retrieved in Integrity bases and Brazilian office. Moreover, they
are highlighted in Table 3 public-private partnerships involved in local production of the drugs listed by the Ministry
of Health.
Table 3. Production Development Partnership signed. Source.
YEAR
PUBLIC
DRUG
PARTNERSHIP PARTNER
Sirolimo
2010
Farmanguinhos
Rituximabe
2012
Biomanguinhos, ivb
Everolimo
2012
Furp, bahiafarma
Mesilato
de
2012
Farmanguinhos
imantinibe
Bevacizumabe
2013
Biomanguinhos,
ivb, butantã, tecpar
L-asparaginase
2013
Fiocruz
PRIVATE PARTNER
CONDITION
Libbs
Bionovis, merck serono
Novartis
Imunossupressor
Antirreumático
Imunossupressor
Cristália
Oncológicos
Orygen, libbs, mabxience,
bionovis, merck serono,
biocad
Nt pharma/ united biotec
Oncológicos; doença
macular relacionada à
idade
Oncológico
Imatinib mesylate
The analysis of data obtained for imatinib mesylate showed that, in principle, they were found at the site of the
Brazilian office 3 documents, of which one was rejected in 2010 and is sub judice; another is on appeal against
rejection. In relation to the third document, n ° PP1100739-7, although dated patent validity fixed at 03/04/2012,
according to art. 230 § 4 of Law No. 9279/96, cannot confirm the termination of this period of validity according to
the information provided by the INPI site. Thus, this is the most advanced partnership project of 6 medications listed
above so far. According to Ministry of Health information, the partnership is in stage 3, i.e. transfer and
internalization of technology and the supply of the product to SUS.
Bevacizumab
Regarding bevacizumab product were recovered in INPI two documents, which one, to remain in force until
17.11.2013, it is sub judice and has been published the filing of administrative nullity; and the second is waiting
analysis after entry into the national phase in the Brazilian office. There is also a PCT deposited whose corresponding
BR was not identified. At the moment of this work in partnership to local production of this drug is in phase
presentation of documents relating to the active pharmaceutical ingredient and the drug ANVISA, in order to obtain
registration. Since this is a newly product launched on the market, clinical studies concerning its application in
leukemia are still scarce, and therefore indications for use in this disease deserves to be accompanied with more
attention.
L-asparaginase
L-asparaginase has three drug patents filed by the Patent Cooperation Treaty (PCT) which are still in the deadline for
submission of documentation with the entry of purpose on a national stage, moving forward the process for grant of
the patent in Brazil. Besides these, there are two other requests, too filed via PCT, which are already under review by
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the Brazilian office. Five of these applications, 4 has its application relates to the treatment of cancer and / or
leukemia. The contract for technology transfer, indicating use in cancer, it was extinguished by Ministry of Health.
However, the technology mapping shown in Table 2 indicates the need for resumption of the agreement, since clinical
studies indicate that among the products in technology transfer process to Brazil, probably this very It will soon be the
most innovative in the market for the treatment of cancer.
Rituximab
According to the information available in the Ministry of Health's website, the contract to manufacture the drug
sirolimus involving partners was not initially approved by the Ministry of Health due to non-compliance with certain
requirements. On time, the partnership is in document presentation stage for the active pharmaceutical ingredient and
the final product to be manufactured by the partners to the organ national regulatory (ANVISA). For this product
found 9 documents the INPI, of which 5 correspond to the first patent the product launched in 1997, which are
already in the public domain in Brazil; a document whose period of validity was fixed until 18.04.2014, is sub judice,
ie, there is an ongoing patent nullity action since October 2013; a document awaiting prior approval of ANVISA;
while another document filed via PCT was received at the national phase in the Brazilian office and pending analysis;
in addition, to a third document contained only information about the filing date in the office. Integrity at the base
were still located 2 documents PCT dated 2012 whose corresponding BR are not yet identified in the site Brazilian
patents.
Everolimus
But the everolimus drug is being delivered to the Ministry of Health to treatment of cancer and immunosuppressive
therapy. Five documents were recovered from patents in the INPI, as follows: 2 patents granted; 2 rejected documents
and thus in public domain; and a document lodged at the national phase in the Brazilian office. There are also 3 PCT
documents whose respective deposits BR were identified in Brazilian site. The everolimus with sirolimus are products
with high chances have indications for use in leukemia corroborated by clinical studies. It appeared Table 2 that these
drugs may appear soon in the list of new products for the treatment of leukemias, adjacent to the L-asparaginase.
CONCLUSION
The mesylate imantinibe already part of the consensus for the therapeutic treatment Chronic Myeloid Leukemia. The
everolimus drug, sirolimus, and rituximab bevacizumab, according to this study, should have its clinical tests for
leukemia closely monitored because local production could be used for pharmaceutical care the Cancer Network.
According to the obtained data, it was observed that the partnership for the production of L-asparaginase could be
revisited in a new light with order to assess the possibility of resuming negotiations for a new partnership focused in
leukemia.Based on the foregoing it is noted that technology mapping studies provide Key information about what are
the advantages and the adoption of certain risks technology. Thus, the technological information should at least be the
basis for planning of public access to medicines policies, especially when they are expensive.
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