Quick takes: Q&A with Marielena Mata on International Activities in Precision Medicine, Biomarkers, and Companion Diagnostics

An interview with Marielena Mata, Director and Diagnostic Lead at Pfizer on International Activities in Precision Medicine, Biomarkers, and Companion Diagnostics

Pfizer is focused on precision medicine as an approach to discovering and developing medicines and vaccines that deliver superior outcomes for patients. Pfizer’s approach is to integrate clinical and molecular information to understand the biological basis of disease, anticipating better selection of disease targets and identification of patient population that demonstrate improved clinical outcomes.

In addition to taking a precision medicine approach to a growing list of therapeutic areas (see Figure 1), Pfizer is also developing expertise in technical areas including biomarkers, deep phenotyping technologies, digital precision medicine, genetics, and health informatics technology (HIT).

Marielena Mata is Director and Diagnostic Lead at Pfizer. She has over 17 years of pharmaceutical industry experience in drug development of biologics and small molecules, companion diagnostics, biomarkers, pharmacology, cell-based assay development, GLP and commercial strategy. Her areas of focus are biomarkers, precision medicine and companion diagnostics in oncology and other therapeutic areas such as infectious diseases and rare diseases. Drawing on her diverse and rich background, Marielena has led partners through the evaluation and implementation of a diverse array of technology platforms for biomarker discovery and development.

Marielena is currently engaged in expanding precision medicine to China, Japan, and Korea, respectively. With her extensive experience working with academic collaborators and third-party vendors, Marielena is dynamic, energetic, and well-suited for her work in international markets.

We spoke with Marielena prior to our asking her to address questions on her work in international markets. We were especially interested in her perspective on the similarities and differences she encounters in the course of her work.


 Pfizer has a long-standing interest in establishing alliances to develop and/or access worldwide capabilities, assets, and opportunities. Along these lines, how do you go about setting up and implementing partnerships in China, Japan, and Korea, respectively? Are there common strategies or does each country require its own approach?

 To answer this question, I’m going to focus on my area of expertise in Companion Diagnostics (CDx) since describing all of Pfizer’s partnering efforts globally would fill a whole book or maybe even an encyclopedia. When developing global companion diagnostic strategies for our drugs, we do look for commonalities in the different regions and markets; in reality, we find in most cases for the three major markets in Asia, each country requires its own approach. For example, the regulatory agencies in Japan (Pharmaceuticals and Medical Devices or PMDA) and Korea (Ministry of Food and Drug Safety or MFDS) have requirements for companion diagnostic submissions similar to those of the FDA but with some differences.

In Japan, for example, the PMDA requires that a Japanese company be the submission sponsor. That frequently results in three-way partnerships with the CDx partner and the local license holder. Furthermore, unlike the US and Korea, Japan does not accept companion diagnostic submissions as a post marketing requirement. The CDx submission needs to be concurrent with the drug submission. That means that all the data for the submission based on Japanese patients, needs to be completed in parallel with the main drug submission.

Meanwhile, in China, the scenarios are different. The National Medical Products Administration (NMPA, formerly the China Food and Drug Administration, CFDA) does not require a CDx submission with precision medicines but diagnostics need to be submitted for NMPA approval. In recent months, there has been a buzz about a guidance for CDx to come out in the new year but for now it is just that, a buzz. In addition, a separate agency in China, the Human Genetic Resources Administration of China (HGRAC) does have specific requirements and approvals for any kind of testing in clinical trials.

To meet all the different regulatory requirements and engage with the different regulatory authorities, we work closely with our local colleagues. We are fortunate in that at Pfizer, as a large transnational pharmaceutical company, we have a strong presence across the globe including the Asia Pacific countries, and we count on local expertise to engage with all the relevant stakeholders. In addition, when identifying diagnostic partners, we take into consideration their expertise in the different markets we are targeting, including regulatory expertise.

 We discussed the need to establish relationships with partners and how partnerships require understanding technical as well as cultural or regulatory need. Could you please discuss how you go about setting up these relationships? For example, what tools or methods do you use to identify unmet medical needs by country? By region?

 As I mentioned before, I am fortunate in that at Pfizer, as a large transnational pharmaceutical company, we have a strong presence across the globe, including the Asian Pacific countries. To deliver on global efforts, we work closely with our local colleagues who have a better understanding of what the unmedical needs are in their country, understand the regulatory requirements and have a view of the local ecosystems for the solutions needed.

My role then becomes assessing whether those local solutions will also support the global needs using clearly defined processes and questionnaires. For example, if we consider local testing for a clinical trial, do the local labs meet CLIA/CAP/GXP requirements so that data can be used in submissions across the globe? The way we conduct these assessments is by visiting and auditing our potential partners as well as training our local colleagues on the global needs so that they can conduct these assessments themselves.

One of the biggest learnings I have had about challenges around unmet needs is the difference in standards of care across countries. Many treatments, and associated tests in the case of precision medicines, are not approved in certain countries, essentially making the patient populations inherently different. This raises the question of whether these patients can be included in global trials.

 What is the status of technology accessibility, e.g., how are urban vs rural clinical laboratories equipped to handle assays, drug delivery, cold-chain supply lines, etc.?

 In my experience, technology accessibility in China, Japan and Korea is similar to that in the US. Large urban areas have advanced laboratory facilities that meet all the quality, regulatory and capacity requirements to serve patients while the more rural areas have restricted access and rely heavily on central lab solutions. In recent years, China has made significant investments in NGS technology and many sites have impressive capabilities, including laboratories with leading-edge technology, manufacturing facilities, and a large capacity for testing.

There is also great investment in building large genetic databases. The year 2018 was very successful in terms of approvals in this space in both Japan and China. Japan approved its first NGS-based tests with companion diagnostic claims in December of 2018 when both the ThermoFisher Oncomine panel and the Foundation Medicine FoundationOne CDx were approved. A third panel, the NCC panel does not have any CDx claims associated with it. In China, Burning Rock and AmoyDx led the race with approvals of small targeted panels for lung cancer.

 You mentioned the Human Genetics Resources Administration of China (HGRAC) in the course of our previous discussions. Could you please explain the function of HGRAC and how you work with them?

 The HGRAC, an agency under the Ministry of Science and Technology (MOST), is responsible for the protection of China’s human genetic resources (HGR) through regulation of the collection and use of any source of genetic material and data. For many years, any source of genetic material has not been able to leave China, and that has limited the inclusion of China in global research. Starting in December of 2017 and as recently as last July, there has been significant changes in the regulatory landscape to enable international collaboration, including the ability to export samples for research.

In short, foreign entities are not allowed to collect or preserve China’s HGR but can request permission to carry out research activities using HGR in collaboration with Chinese institutions. A joint application is filed with detailed information of the research to be conducted, the number of samples to be collected, any information on data sample size and all research agreements signed. Every party involved in the collaboration (sponsor, diagnostic partner, testing lab, academic collaborator) needs to sign the application and assume responsibility for all aspects of the study.

There are also requirements for IP sharing with Chinese academic institutions. The submission process is relatively simple, and their review is efficient but some of the requirements present a challenge for the way we frequently conduct research. For example, the HGRAC submissions requires that all research agreements are submitted but frequently, we have not identified the technologies or vendors that we want to use for certain analyses as we might want to wait to set up some of those agreements at the end of the trial for retrospective analysis of biomarkers.

Additionally, there is a strong focus by the HGRAC on sample numbers and data size that must be carefully justified during the application without room for biobanking or sample collection for research that has not been defined. This approach leaves no room for implementing more exploratory approaches using new technologies that might emerge after the completion of the trial.

 Do Korea and Japan have a similar group? Other countries in Southeast Asia?

 The HGRAC appears to be unique to China though other countries may have similar requirements around local testing, local entities sponsoring submissions, etc.

 Does HGRAC contain population profile data that you can access (e.g., health, records, economic status, local access to clinics, etc.)?

 One of the responsibilities of the MOST is to gather genetic data of specific populations but that data is protected and not accessible by foreign entities.

 We also discussed issues with communication, not so much the language but, e.g., simply arranging a meeting across 12 hours difference in time zones. What are the major areas to note here – language, social mores, age, gender, hierarchy status? All of the above?

 We all agree that communication is key for any team’s success but communication with our Asia colleagues raises some additional challenges. If we start with the basics – time zones – setting up meetings is a challenge as someone is going to call into the meeting before their working hours (and potentially before coffee, gasp!) and someone is calling late at night.

There is a narrow window of opportunity and a long list of conflicts, making it difficult to find that sweet spot. So now, you are all on the telecom and language barriers come into the picture. Fortunately for me, my colleagues in China and Japan speak much better English than I speak their language, but some things are lost in translation and due to accents and comprehension of slang terms and casual language (i.e. sweet spot, a sports reference!), we spend a lot of time repeating ourselves and clarifying statements.

Some could argue that e-mail may be a better tool at this point, but the time factor needs to be taken into consideration. I can write an e-mail at the beginning of my day, when they are getting ready for bed, and my colleagues will not read it and reply until I am home that evening. Unless I check my e-mails in the evening, I won’t see it until next morning. A whole 24 hours have gone by leaving little to no room for a meaningful back and forth discussion over e-mail.

Social norms also vary significantly between cultures and I am sure my colleagues think I am really rude with my succinct, one-line e-mails and always being 5 minutes late to the call because of another meeting. How do my colleagues in Japan and China always seem to be ready to go 3 minutes early and not be out of breath?

Protocol and hierarchy play a big role in those societies and it can take a while to find a happy medium to accommodate all members of a global team. I am happy to report though, that despite reports on gender disparities, I have not observed that in my interactions with China, Japan and Korea. In fact, in all my experiences, I have had the pleasure of working with very talented, respectful and supportive men and women.

 What advice do you have for those starting out in these countries? Could you provide two or three other lessons learned? what would you have liked to have known when you started?

 Focus on relationships and understanding your team’s needs from a cultural and communication perspective. Understanding those aspects will facilitate learning about and understanding their regulatory systems and medical needs.

In retrospect, I would have liked to have known that though it is a challenging experience to work from afar, I truly enjoy working with my colleagues in Asia to find solutions for patients and that many of my prior preconceptions were wrong. I have learned so much in the last couple of years about similarities and differences in needs, processes and potential solutions to the different challenges presented.

I also would have liked to know that the environment and therefore, requirements, are constantly changing and we need to remain open and alert to the constant change. There is significant investment in Asia in biotechnology, and state of the art capabilities are there to be explored and utilized. Not every solution needs to come from the US but we need to keep an open mind to local solutions that are already designed to address local needs.

 Any parting thoughts?

 The environment in Asia is very dynamic regarding regulations for drug development, precision medicines and diagnostics. Changes come fast and you have to remain nimble, but the reward is knowing that you are bringing solutions to millions of patients in these growing markets. Keep an open mind, be patient, be flexible and don’t forget your sense of humor. Remember, the patients are waiting.

Background on Pfizer precision medicine

As a key R&D platform, we’re investing in precision medicine across our organization, building on experience in oncology to expand the benefits of precision medicine in other areas such as rare disease and immunology. In our portfolio, we’re focused on exploring genetic, phenotypic and functional biomarkers to identify target populations that will guide clinical strategies.

This concept has been most fully explored in oncology, where we’ve been able to accelerate development of targeted therapies in non-small cell lung cancer by identifying a molecularly defined cohort of patients who would benefit most and are currently focusing on further expanding our understanding of molecular mechanisms underlying immuno-oncology therapies. A few examples from other diseases: Hemophilia, Inflammatory Diseases, Novel Targets, 23andMe.

Lessons Learned

• A major challenge around unmet needs is the difference in standards of care across countries. Many treatments, and associated tests, are not approved in certain countries, essentially making the patient populations inherently different. This raises the question of whether these patients can be included in global trials.

• Focus on relationships and understanding your team’s needs from a cultural and communication perspective. Understanding those aspects will facilitate learning about and understanding their regulatory systems and medical needs.

• Be aware that environments and standards are constantly changing. Keep up to date on these topics.

• Keep an open mind to local solutions that are already designed to address local needs – not all solutions need to come from one’s own country or company.

• Be prepared to question prior assumptions and preconceptions – especially about similarities and differences in needs, processes, and potential solutions to different challenges.

• Although it is challenging to work with colleagues from afar, one can find enjoyment in working with these colleagues to find solutions for patients.


Marielena Mata, Ph.D.
is Director and Diagnostic Lead at Pfizer, where she leads the development and commercialization efforts of companion diagnostics for Oncology assets from early to late development. Prior to Pfizer, Maty was Head of  Personalized Medicine and Companion Diagnostics at GSK where she was responsible for implementation of the Precision Medicine strategy across the GSK portfolio encompassing technical, development, regulatory, commercial, IP and business development efforts.  Previously, at Janssen R&D, Inc.  Dr. Mata was responsible for the design and implementation of biomarker strategies for Oncology assets, where she led the development of Circulating Tumor Cell based assays as companion diagnostics as well as the development of next generation circulating tumor cell isolation technologies based on microfluidics.  Earlier, she established and managed the Biomarkers biobank.   Dr. Mata obtained a B.A. in Biology at the University of North Carolina at Greensboro and her Ph.D. and postdoctoral training in Immunology at the University of Pennsylvania.

References

1. Alliances capabilities, assets, or opportunities to enable Precision Medicine strategies: Patient cohorts, Systems Biology/Pharmacology, Breakthrough diagnostic technologies, In vivo imaging technologies, Biospecimen Analysis, iPS cell resources and technologies.

2. Human Genetic Resources Administration of China (HGRAC): As per the MgmtHumanGen and S&T-HGRExportLicense, HGRAC is responsible for reviewing and approving applications to collect and export human genetic materials. According to the MgmtHumanGen, the HGRAC was jointly established by the Ministry of Science and Technology (MOST) and the Ministry of Health (renamed the National Health Commission (NHC) of the People’s Republic of China) within the State Council of the People’s Republic of China. In addition, the HGRAC is tasked with reviewing and approving applications submitted by any Chinese collaborating party interested in conducting international collaborative projects involving human genetic resources in China. The HGRAC reviews these applications to engage in international collaborative projects and the applications to export human genetic materials on a quarterly basis.