Pharma research requires access to materials from today\'s gold standard of medical care to discover the next generation of therapeutics. This need is increasing in the upcoming area of personalized medicine. Collaboration with MDs and their ethic committees is crucial to built up a pharma research biobank, as is the willingness of patients to donate samples. Success in this strategic area of operations requires multi-dimensional skills.
Rationale for pharma biobanking
Despite significant advances, there is still need for better, highly effective and well-tolerated therapies for many indications. This requires the collaboration of scientists, clinicians and basic researchers from academic as well as industrial research. It is practically impossible to generate new knowledge on diseases without relevant patients’ tissue materials. Patient material is essential for microscopic, cell biological and molecular studies. It is of decisive advantage if research projects can resort to already existing samples, which has frequently only been sporadically possible if any material from an old study is available. It is then critical whether the newly planned uses of these samples are covered by the original ethics vote, the patient information and consent.
How can compliance with such a sensitive topic be assured in a research environment?
Is the access to biospecimens aligned with novel strategic goals and effectively organised?
Which challenges emerge by the focus of multinational pharma companies shifting to Asia?
The process of high quality generation, logistics, storage and processing of samples from patients is summarised in the term "biobanking", defined as "organised biological sample collections with associated personal and clinical data". While this can be achieved without major problems in the GCP setting of a clinical trial, even at a multicentric scale across borders, this is already a challenge for a research department. Personalised medicine increases the need for specimens further, as illustrated in the following by some oncology examples. Oncology is a major indication for biomarker activities, since the somatic alterations driving tumour growth are individual hallmarks of each patient. Histological description of the tissue morphology is inadequate in describing the tumour, a molecular understanding is needed for clinical success. Therefore, the signalling networks identified in the last decade have morphed from a playground for biologists into a battle ground for pharma companies, which are competing for recruiting patients to clinical trials of inhibitors for identical or functionally interlinked targets such as from the PI3K and neighbouring pathways.
Frequently, markers require more finicky sample types than DNA, for example tissue samples for immunohistochemistry. Where tissues are unavailable, for example from patients with relapse after tumour resection and standard chemotherapy, circulating tumour cells might provide crucial information on the current status of the systemic disease characterised by unresectable biopsies. However, these specimens have to be analysed with specialised equipment within a few days after generation.
The recent paper by Mok et al. highlights the importance of global biomarker activities for a globally operating pharma company – the prevalence of a marker crucial for prediction of therapeutic success was found increased in patients of Asian descent vs. Caucasians. Even if the marker in question is a DNA based marker, namely somatic mutations in EGFR, it can only be analysed in diseased tissues, in contrast to pharmacogenomics markers which comparatively simply require DNA from a buccal swab.
Practical experiences in building up a biobank for biomarker research
Among joint biobank studies of MDs and PhDs, one can distinguish those carried out with or without support from contract research organisations (CROs). Furthermore, a prospective study has to be regarded differently from a retrospective analysis of historic legacy samples and data, leading essentially to four different scenarios.
A feasible way to start scientific research on human biospecimens quickly is obtaining legacy samples from a CRO, reimbursing their efforts. Commercial companies had originally a pioneering role in building up biobanks. However, the emergence of commercial biobanks led also to questions regarding the ethical and legal aspects. Purely commercial biobanks are not without controversy. Meanwhile, it is usually believed that the involvement of commercial partners is not objectionable if compliance with the rules of scientific and social norms is respected. Audits can ensure compliance of the external partner to the applicable guidelines and contractual obligations.
However, the needs of the pharmaceutical industry often preclude use of this strategy. For example, surrogate biomarker research in oncology requires blood samples matching to excised diseased tissue. These biofluids are usually not collected or not conserved in standard practice and thus not available from historic cases. Furthermore, even if samples exist which match the desired scientific profile, their use for research has to respect the patients from which they origin. If there is no informed consent for research purposes at all or it does not cover the intended work plan, then realisation of the intended research becomes challenging. The general situation is even worse in indications beyond oncology such as women’s health care or cardiovascular diseases, where hardly any biobanking CROs operate and their expertise rarely covers the specialised requirements.
Our collaborative approach built on mutual strengths of MDs and PhDs
In contrast, a joint MD / PhD prospective methods study can be custom designed to meet today’s research needs, but this might take some time. This might be explained by the cultural differences between the two partners and the need to understand each other’s situation and needs. Also the complexity of the contractual framework to be negotiated by the legal departments of the two entities has to be mentioned. A CRO can hardly improve this initial situation, but be instrumental in the operations phase of a study, such as the preparation of the sampling tubes, checking clinical data, for delivery of liquid nitrogen or transportation of the samples provided. This is, however, marginally to the critical role of the MDs’ and nurses’ motivation. Only they have access to the patients, can contact them for enrolment, obtain the informed consent, process the samples and fill in the case response forms. The researchers can only try to convince the medical personnel to schedule this additional task in their busy agenda of the public health system’s hospitals. Ideally, the physician is interested in the data only the researcher can obtain via his or hers bioanalytical capabilities. This results in a self-interest of the clinician to provide high quality specimens.
The interest of clinicians in a scientific collaboration can best be triggered by explaining the rationale, for example, giving a lecture or presentation to a medical audience using the poster session of a scientific conference. The researcher should also take the opportunity to convince the clinician of his professional expertise in dealing with clinical specimens. This starts with the way the samples are taken care of. Unique barcodes clearly document the history of samples and specimens. Excellent logistics is a key success factor. Many biological analytes are unstable and are damaged by repeated freezing and thawing. Aliquoting achieves that the final aliquot is as often thawed as the first, namely just two times: once for aliquoting and then for analysis. The combination of different samples on microtiter plates results in a collective that is measured in each measurement at the same time so that measurement problems such as day-to-day variation are eliminated, in accordance with the international guideline on validation of analytical procedures for registration of pharmaceuticals for human use. Thus, individual samples are portioned in e.g. 96 well format plates and a stack of those plates is used not just for a single but several measurements, dramatically increasing the "yield" of data from a specimen. These opportunities arise from experience in automated material banks serving small molecule compound libraries and the high throughput screening departments which the pharmaceutical companies established in the past. In addition, miniaturisation by more sensitive techniques and multiplexed analytical methods can multiply the number of analytical parameters to be measured in a given sample volume. Best practice to control pre-analytical variation is here shared by conferences and trade shows, publications and, increasingly, publishing SOPs on homepages of institutions such as ISBER or NCI’s OBBR.
Correlating experimental results to clinical data can lead to peer- reviewed publication. Industrial biomarker research is more freely publishable than articles describing targets or compounds. A joint MD / PhD author list acknowledges each partners’ contribution to the common work. We therefore advocate a model of partnership between industry and academia, in which the strengths of different institutions are combined with the goal of using excellent clinical material to extract as much analytical data as possible and even to make the results available to the scientific community. In this interdisciplinary field, personal skills become crucial for success of this partnering model. We thus favour an emerging public-private partnership model of pharmaceutical research based on complementary synergies resulting in mutual benefit.
The Asian perspective
The raising awareness of pharma companies to provide innovative treatments to Asian patients leads to the requirement of their research departments to have access to samples from the local populations. The best practice of biobanking should therefore also be deployed in Asian countries. The leading academic biobanking society, ISBER, held an international symposium in Korea already in 2009. Interestingly, India’s IT industry has generated a software package even for biobanking. Ocimum’s relational database solution, biotracker, is according to the vendor’s homepage capable of supporting typical tasks of biobanking, such as clinical data, specimen data, tissue micro arrays, inventory and request management.
A wave of Asians who went to university abroad and then joined western pharma companies have returned to their home countries as professionals and can act in their new positions as inter-cultural ambassadors and, if now in an academic role, can educate a new generation of scientists in best practice. They can work together with pharma companies and perform research studies on their behalf in countries which restrict export of biospecimens.
This is the most recent wave of Asians who for centuries have migrated globally, facilitated by trading relationships. Many of their descendants have settled down, not only in the US, but also in Commonwealth countries such as Canada or Australia. As some of these individuals are afflicted by cardiovascular diseases or cancer, they become patients of Asian progeny in a western legal and healthcare system and their specimens and associated clinical data might become valuable for understanding to which extent genetic predisposition vs. environmental factors contributed to their diseases.
The next challenge will be to bring the benefits of biomarker-supported pharma research to Asian patients beyond oncology, in areas such as cardiovascular diseases or woman’s health care. Also for this reason, Bayer Healthcare’s pharma division opened a research and development centre in China in 2009. Changing demographics and life styles have brought such indications to increased awareness of Asian countries’ inhabitants and health systems alike, requiring among others novel biospecimen-based research. Our collaborative approach to translational medicine will go global, requiring intercultural skills.
Acknowledgements
This article is partly based on a forthcoming book chapter regarding research biobanking authored with J. Swifka and K. Asadullah. I would also like to thank all external and internal partners involved. All opinions expressed are the author’s personal views.
Legal framework of biobanks for research purposes
The main ethical and legal aspects related to biobanking can be distinguished from a legal point of view in the three consent levels involved: ownership of the body material; personal data; and informational self-determination and general personal rights. They cover aspects of patient education / patient consent (informed consent), confidentiality / anonymity, the potential multiple use of the material and the data over time, access to the results, and the sharing of data. From a practical point of view, the collection and storage of samples and associated clinical data in a human clinical prospective research methodology study affects primarily the doctor-patient relationship, privacy and safety at work. Good professional conduct of the physician requires that such studies are approved by the relevant ethics committee. Similar to a clinical trial, patient information, informed consent, and the study plan have to be submitted. It is crucial that the intended use of samples and data is on the one hand exactly, but on the other hand as far reaching as feasible described in the patient information and the consent form. The consent of the patient has to be documented by signature.
The clinical data then are pseudonymised or completely anonymised for research use. Anonymissation has the advantage that it eliminates the data protection concerns. Frequent is a collaboration between a clinician and a scientist who analyses the samples. Typically, the researcher does not receive the full name but solely the initials or even just a patient identification number in this study (not the hospital’s patient ID), neither the address or place or date of birth (only the year of birth). The key allowing reidentification of the study participant remains with the clinician. In a narrow sense, this process is pseudonymisation; however, there is a general opinion in the literature that this process can even lead to anonymisation, in particular where MD and PhD belong to two different legal entities. Finally, compliance regulations also require companies to assess the health risks for their employees during storage, processing or disposal of clinical samples. The necessary risk assessment considers the risks for the technicians associated with processing the samples based on the type of samples and the information available regarding the donors’ health.
Author BIO
Arndt Schmitz joined the pharmaceutical industry in 2001 after a post doc in the US. He was a biotech group leader prior to founding the Research Biobank. He is also Senior Scientist in Global Biomarker Research of Bayer Healthcare’s Pharma Division. He has contributed to international conferences covering these topics.
Robert W Esmond's intellectual property law experience has principally been in the biotechnology and chemical areas. His legal experience includes counseling clients in various intellectual property matters such as patentability investigations, validity and infringement analyses, freedom to operate and FDA/ANDA practice.
