Newsletter Summer 2018 - 06/21/2018





Newsletter – Summer 2018


By Thomas Seoh

President and Chief Executive officer

                    This email address is being protected from spambots. You need JavaScript enabled to view it.

Dear Friends of Kinexum,

Welcome to the Summer 2018 Kinexum Newsletter!  

We have three expert guest authors:  (i) Professor Lutz Heinemann discusses the status of biosimilar insulins; (ii) Rob Claar describes fast-track opportunities for development of stem cells and other advanced therapies in Japan; and (iii) Dr. Bart Van der Schueren, Belgian representative to the EMA, reflects on key differentiators between the EMA and the FDA.  In addition, our Lana Pauls contrasts her experiences at the FDA, at IQVIA, the world’s largest CRO, and at Kinexum. 

 (read more) 


ByLutz Heinemann, PhD, Science Consulting in Diabetes GmbH, Neuss Germany

                       This email address is being protected from spambots. You need JavaScript enabled to view it.


In view of the high number of patients with diabetes who regularly need subcutaneous insulin injections, it is obvious that the market for the different insulin formulations is huge, well above $5 billion on a worldwide basis. Until recently, three pharmaceutical companies (Eli Lilly, Novo Nordisk, and Sanofi) dominated this market. Because patent protection for human insulin and some insulin analogues that have been developed by these companies in the past has expired, “copies” of such insulins can be brought to the market.

(read more)


ByLana Pauls, MPH

              Regulatory, Clinical Operations and Project                            Management, Kinexum

                This email address is being protected from spambots. You need JavaScript enabled to view it.

 I joined Kinexum earlier this year, filling two roles:

Director, Client Engagement, and

Consultant, focusing on regulatory affairs, regulatory strategy, CTD submission development, and project management

The purpose of this article is to compare and contrast my regulatory perspective and experiences over the three VERY DIFFERENT roles I have played over the past three decades.

(read more)                                                                                               

FROM KINEXUM FOUNDER: A tale of two different scientific worlds

By Alexander Fleming, Executive Chairman

  This email address is being protected from spambots. You need JavaScript enabled to view it.

  A number of Kinexers, myself included, are about to make the annual pilgrimage to the American Diabetes Association meeting where we will be immersed in the cacophony of basic science and clinical data, technologies spanning nutrition, drugs, biologics, devices, and digital products, and commercialism.

It is quite remarkable to behold the impact of a hormonal deficiency state on so many people and the responses of our professional, industrial, and commercial infrastructures to this disorder.  Diabetes is big business, big science and medicine, and once a year in the US, a big meeting.  (Read more)

Fast track OPPORTUNITIES in Japan for Regenerative Medical Products

By Robert E. Claar, CEO of Hekabio KK

                                This email address is being protected from spambots. You need JavaScript enabled to view it.

 Kyoto University professor Shinya Yamanaka co-won the 2012 Nobel Prize in physiology or medicine for his 2006 discovery that mature cells in mice could be reprogrammed and induced to become immature and pluripotent stem cells (iPS cells). This dramatically accelerated what was already a nascent revolution in Japan for regenerative medicine. New legislation was created, government and private funds became available, new companies and industry associations sprung up and old companies entered this new field.

(


The European Regulatory Framework: personal perspectives.

By Dr. Bart Van der Schueren

IG Endocrinologie UZ Leuven

                  This email address is being protected from spambots. You need JavaScript enabled to view it.

   Regulating drugs is challenging as it involves competing interests:  on the one hand regulatory bodies need to ensure that medicinal products are both safe and effective; on the other, there is intense pressure for innovative therapies to reach patients as soon as they are available.

European regulators rightly understood that harmonization was needed between its 28 (soon to be 27 because of Brexit) member states in terms of the requirements to obtain marketing authorization. 

(read more)

Note from Kinexum CEO (cont.) …


We welcome David Brill, a US/European regulatory affairs expert who spent some decades at Boehringer Ingelheim, and Kinexum Associate Jennifer Zhao, a magna cum laude graduate of the Dartmouth College Class of 2018, who begins an initial one year stint with us in July.


Rob Claar presented on his topic in a Kinexum webcast earlier this month, and Bart Van der Schueren will present on July 13, and we will have a future webcast on US and EU regulation of advanced therapies.  Recordings and slides of our webcasts are available on our website.  Also, our Fall Newsletter will contain a follow up piece on CMC aspects of advanced therapies.  Please - we would love any feedback on your interest level and value to you of these articles and webcasts.



From Kinexum Founder: A Tale of Two Different (cont.) …

I will go on from Orlando to a very different scene, the annual meeting of the American Aging Association (AGE) and American Federation of Aging Research in Philadelphia, where I will address the assembly on “Blazing clinical development and regulatory pathways for healthspan interventions.”  See

The AGE meeting consists mainly of basic scientists who utilize in vitro and animal models to discover and characterize candidate agents for extending lifespan. It is a much smaller scientific community with little corporate support. It’s a much smaller meeting than ADA’s.  The diabetes and healthy lifespan worlds could not be more different even though virtually every older adult has keen interest in the subject of anti-aging treatments, and many products with a healthy aging message are on the market.  Some high-powered companies, like Google’s Calico, have signed up for a moonshot-like commitment to finding lifespan interventions. But, compared to diabetes, the anti-aging world has very limited R&D going on. 

The most important reason for this tale of two different scientific worlds is simply economic—lack of incentives for investing in an enterprise that will lead to valuable products. Development and regulatory pathways for drug-like, healthy lifespan products remain to be established.   Until they are, our society will continue to pay for a lot of products with a good story but little data for to support safety and effectiveness.  It is not an easy challenge to solve because lifespan therapies will require more time and money to show safety and effectiveness than treatments for diabetes or other chronic illnesses.   

There are ways forward.  One good example is the TAME trial (Targeting Aging with Metformin), led by Nir Barzilai and supported by Kinexum.  TAME serves as a model for combining multiple, age-related conditions together, including cancer, cardiovascular disease and Alzheimer’s disease, in a single composite efficacy endpoint that, if positive, could support a healthy lifespan indication.  Metformin has been around a long time. No one is going to make a lot of money on metformin, even if it is approved for this indication.  But, since we have abundant evidence of metformin’s safety and epidemiologic evidence of efficacy against each of those conditions, it represents the low hanging fruit among all the potential interventions for healthy aging.  A related example with great promise is NuSirt and its combination of approved agents with accumulating clinical evidence of dramatic pharmacologic synergy in lowering blood glucose, lipids, hepatic fat, body weight and blood pressure.  NuSirt, also supported by Kinexum, is targeting the standard disease indications related to the above effects, but I believe a NuSirt product would perform very well in a TAME-like trial. 

New molecular entities will generally have to be approved or at least have data for disease indications before they can be aimed at lifespan indications, but TAME does present a development pathway.  Is that also a regulatory pathway?  We shall see, but we at Kinexum want to help in blazing that pathway.  Kinexum has and will continue to support this field in other ways.  We bring a wide range of expertise in scientific benchmarking, clinical trial design, measurement technology (functional and patient reported), and working with FDA and other stakeholders to address the key challenges.  Kinexum will also continue to advance the concept of Metabesity—the constellation of major chronic disorders (cancer, dementia, obesity-diabetes, cardiovascular disease and the aging process itself)—with common, metabolic roots.  The London Metabesity Congress last October was a terrific start to what we envision as an annual multidisciplinary gathering of experts and stakeholders who come together to work for preventions of Metabesity. 

With summer about to officially begin, I wish our friends and colleagues a season of health and re-creation.



Lutz Heinemann, Ph.D., Biosimilar Insulins (cont.) …

As it is not possible to manufacture truly identical copies of complex proteins by biotechnological processes (“the process is the product”), a much more thorough evaluation of insulins manufactured by new companies has to be performed in comparison to generics (= small molecules manufactured by means of chemical synthesis). Therefore, the guidelines provided by regulatory agencies for market approval of such “biosimilar” products are quite detailed, with a strong focus on manufacturing details. From a clinical point of view, the main requirements are to demonstrate similarity of the pharmacodynamic and pharmacokinetic properties of the “biosimilar” insulin formulation in comparison to the originator insulin. This can be shown in well-performed euglycemic glucose clamp studies. Such studies must be performed in patients with diabetes. However, no large Phase II and Phase III clinical trials with large numbers of patients are needed. It also must be shown that these insulins do not induce formation of insulin antibodies above the level of the originator insulin.  Reasons for immunological concerns are impurities in the formulations and/or e.g. glycosylations of the insulins that are induced by the manufacturing process.


Once such insulins are approved as biosimilar insulins (also referred to as BioIns) and can be launched (see below), they enter a market with well-established players who are fighting for market share.  Gaining market share will be driven by factors such as cost advantages and political pressure. Currently >20 companies have biosimilar insulins in clinical development. It will remain to be seen how many will ultimately come to the market; however, most probably a plethora of e.g. insulin glargines might be on the market within some years, which could generate some confusion both among patients and among healthcare professionals.


Approved biosimilar insulins: Basaglar


The first approved biosimilar insulin – an insulin glargine developed by Eli Lilly and Boehringer Ingelheim (Abasaglar® in the EU and Basaglar in the US®) – has been on the market now for 1-2 years in the EU and the US.  However, there has not yet been a general landslide in favour of this more affordable insulin.  Nevertheless, it has gained significant market share in some countries in the EU. The decrease in prices observed varies among such countries, with a maximum price drop of up to 30%.


Approved biosimilar insulins: Admelog


More recently, the first biosimilar insulin (Admelog®) of a rapid-acting insulin analog (insulin lispro) - developed by Sanofi - was approved in the US and the EU. Studies with patients with type 1 or type 2 diabetes were published and it is on the market on both continents now [1, 2]. Also, data about the risk of developing insulin antibodies [3] and when this biosimilar insulin is used in insulin pumps [4] were published, showing no difference in the properties of this biosimilar insulin, compared to the originator insulin.


Approved biosimilar insulins: Lusduna


The next biosimilar insulin that most probably will come to the market in the EU and the US is another insulin glargine developed by Merck-US (Lusduna®). Merck has secured approval by the FDA for their version of insulin glargine; however, they refrained from launching it as they are blocked by a law suit against them by Sanofi. In the past, Eli Lilly was able to get a settlement deal with Sanofi for their biosimilar insulin Basaglar. However, Merck recently published the results of clinical trials in patients with type 1 diabetes or type 2 diabetes with their insulin glargine [5, 6].


Non-approved biosimilar insulin by Mylan / Biocon


A biosimilar insulin that most probably will come to the market is the insulin glargine being developed by US-based generics giant Mylan in cooperation with the huge Indian pharmaceutical company, BioCon. However, both EU and FDA inspectors independently raised concerns about the production facility in India. Nevertheless, both companies are confident that they can solve the issues and that they are progressing according to their plans for the launch of this biosimilar insulin.  Mylan had filed an application to the FDA for their insulin glargine in pre-filled pen and vial forms under the 505(b)(2) regulatory pathway, which enables a faster than usual regulatory approval process, partly relying on the data already generated by a previous drug maker. This approval process was created by the Hatch-Waxman Amendments of 1984 as part of the Federal Food, Drugs and Cosmetics Act.  The aim was to allow entry of differentiated drugs that offer alternatives at an accelerated pace and avoid duplication of existing safety and efficacy data.  Again, Sanofi is not willing to give up rights on its originator insulin glargine, which is a billion dollar drug for them. Thus, Sanofi filed a lawsuit against Mylan in the US alleging infringement of its patents.




As stated, until now market introduction of biosimilar insulins has not resulted in drastic changes in the insulin market; however, as more biosimilar insulins enter the market, the increase in competition will most probably change this rapidly [7]. We will have to see if the prices start a race to the bottom as in the case of test strips for blood glucose measurement systems, which took place in recent years. This will also depend on the pressure to lower insulin prices by insurance companies and/or government healthcare systems. It is of interest to note that prices for originator insulins – which have substantially gone up especially in the US in recent years – have not be solely driven up by the manufacturers, but also by pharmacy benefit managers [8, 9].  Another question is whether one or more biosimilar insulins will get approval by the FDA for interchangeability, and qualify for automatic substitution at the pharmacy level of a lower priced biosimilar insulin with comparable properties (see below).


Immunological aspects


A matter of concern is the question if biosimilar insulins might differ in their immunogenic properties from the originator insulin. The approval requirement of a clinical study with a limited number of subjects (300) over a limited period of time (6/12 months) might not be able to clarify if such reactions do show up in certain patient groups over a prolonged period of usage. A major concern is that – at least in the case of some patients – formation of (neutralizing) insulin antibodies is stimulated. Differences in immunological responses might be induced by certain differences between the biosimilar insulins and the originator insulin [3, 10].




Another important question is the quality of different batches of originator and biosimilar insulins over time.  Insulin is manufactured in batches, which could differ considerably from each other as a reflection of the complexity of the manufacturing process.  The amount of information that companies are reporting about this topic is quite limited [11, 12].




Switching from one insulin to another for a given patient is a decision made by the treating physician [13].  Interchangeability means the practice of changing one insulin for another that is expected to achieve the same blood glucose lowering effect in any patient with diabetes on the initiative or with the agreement of the physician. This requires that the insulin can be regarded as interchangeable, i.e. as a property of a given insulin. The FDA has relatively lately characterized what their expectations are for such a label; however, until now no biosimilar insulin has received such a label. In contrast, substitution is a process at the pharmacy level without (!) consulting the prescribing physician whereby a biosimilar insulin is dispensed instead of the prescribed insulin.  Currently, there is no “substitutability determination” in the EU, i.e., there is no automatic substitution in practice in the EU whereby a pharmacist is obliged to dispense a biosimilar insulin instead of a prescribed insulin.  Interesting differences exist between states in the US when it comes to guidelines for market allowance of biosimilar insulins.




In daily practice for patients, diabetologists and nurses, the devices (most often insulin pens) used for application of insulin are of high relevance.  Each manufacturer of biosimliar insulins comes to the market with a combination of e.g. their insulin glargine with an insulin pen, which – as indicated – is associated with a certain risk of confusion.  The switch from the pen(s) of the originator insulin to another one is associated with an additional teaching and training burden for the diabetes team. Such aspects are of high relevance from a practical point of view.




These are early days for biosimilar insulins.  They will without doubt gain more attention and momentum in coming years, mainly driven by lower cost.  Lower insulin prices in turn mean more patients can afford and gain access to some form(s) of safe and effective insulin [14].




 ADDIN EN.REFLIST 1.         Garg, S.K., et al., Efficacy and Safety of Biosimilar SAR342434 Insulin Lispro in Adults with Type 1 Diabetes Also      Using Insulin Glargine-SORELLA 1 Study. Diabetes Technol Ther, 2017. 19(9): p. 516-526.

2.         Derwahl, K.M., et al., Efficacy and Safety of Biosimilar SAR342434 Insulin Lispro in Adults with Type 2 Diabetes, Also Using Insulin Glargine: SORELLA 2 Study. Diabetes Technol Ther, 2018. 20(1): p. 49-58.

3.         Home, P., et al., Anti-Insulin Antibodies and Adverse Events with Biosimilar Insulin Lispro Compared with Humalog Insulin Lispro in People with Diabetes. Diabetes Technol Ther, 2018. 20(2): p. 160-170.

4.         Thrasher, J., et al., Safety of Insulin Lispro and a Biosimilar Insulin Lispro When Administered Through an Insulin Pump. J Diabetes Sci Technol, 2018. 12(3): p. 680-686.

5.         Home, P.D., et al., Efficacy and safety of MK-1293 insulin glargine compared with originator insulin glargine (Lantus) in type 1 diabetes: a randomized, open-label clinical trial. Diabetes Obes Metab, 2018.

6.         Hollander, P.A., et al., Efficacy and safety of MK-1293 insulin glargine compared with originator insulin glargine (Lantus) in type 2 diabetes: a randomized, open-label clinical trial. Diabetes Obes Metab, 2018.

7.         Heinemann, L. and A.W. Carter, Will Biosimilar Insulins Be Cheaper? Diabetes Technol Ther, 2017. 19(9): p. 513-515.

8.         Carter, A.W. and L. Heinemann, If PBMs Guard Access to Drugs, Then Quis Custodiet Ipsos Custodies? (Who Will Guard the Guardians?). J Diabetes Sci Technol, 2016.

9.         Carter, A.W., In the Biosimilar Marketplace Will There Be 50 Ways to Leave Your Insulin? J Diabetes Sci Technol, 2016.

10.        Owens, D.R., et al., The emergence of biosimilar insulin preparations--a cause for concern? Diabetes Technol. Ther, 2012. 14(11): p. 989-996.

11.        Carter, A.W., L. Heinemann, and D.C. Klonoff, Quality Control of Insulins and Biosimilar Insulins: What Do We Know? J Diabetes Sci Technol, 2016. 10(4): p. 811-815.

12.        Carter, A.W. and L. Heinemann, Insulin Concentration in Vials Randomly Purchased in Pharmacies in the United States: Considerable Loss in the Cold Supply Chain. J Diabetes Sci Technol, 2017: p. 1932296817747292.

13.        Dowlat, H.A., et al., Interchangeability among reference insulin analogues and their biosimilars: regulatory framework, study design and clinical implications. Diabetes Obes. Metab, 2016.

14.        Perrin, C., M. Ewen, and D. Beran, The role of biosimilar manufacturers in improving access to insulin globally. Lancet Diabetes Endocrinol, 2017.


Robert Claar, Opportunities in Japan (cont.) …

Human iPS cells were first implanted for the treatment of age-related macular degeneration (autologous implant in September of 2014 and allogeneic transplant in March of 2017). Additional iPS cell clinical trials were approved in Japan for Parkinson’s disease in 2017 and severe ischemic cardiomyopathy in 2018, with more programs under development, including for thrombocytopenia and spinal cord injury.

Breakthrough research in iPS cells is what got this started, but that is not the whole story. This article explores the current status of regulations and opportunities in Japan. The environment has now been established for fast-tracked clinical research and approvals in the regenerative medical field. What does that mean for companies in Japan and companies interested in coming here to accelerate their development programs?

In November of 2013, Japan announced new regulations which became law in November of 2014. The new Act on Pharmaceuticals and Medical Devices (PMD Act) established regenerative medical products (RMPs) as a distinct third category, after drugs and devices. A new office was established for the review and regulation of this new category in the Pharmaceuticals and Medical Devices Agency (PMDA): the Office of Cellular and Tissue-based Products.


RMPs are defined as processed (more than minimal manipulation) live human or animal cells that are intended to be used for the reconstruction, repair, or formation of structures or functions of the human body, the treatment or prevention of human diseases or for gene therapy.


The goal of the RMP inclusion in the PMD Act was specifically to enable early conditional approvals. Now, conditional approval is possible based on a limited number of cases to ‘demonstrate safety and anticipate efficacy’, while ongoing evidence can be studied in post-marketing registration studies within 7 years from conditional approval.


The stated goal is to enable treatment access for patients with unmet medical needs. Certainly, the government of Japan was also very keen to trigger economic growth based on the Yamanaka effect, and wanted to create a framework that enabled speedy but safe development for RMPs.


At the same time as the PMD Act, Japan created the Act on the Safety of Regenerative Medicine (Safety Act) under regulation by the Ministry of Health, Labour and Welfare (MHLW). The goal of the Safety Act is also very clear. Japan needed to rein in potentially unsafe practices at cosmetic and other clinics where doctors were administering to patients willing to pay for expensive, unproven stem cell therapies and cancer vaccines, etc. The Safety Act doesn’t outlaw these practices, but requires that all facilities and programs be properly registered.


The Safety Act categorizes RMP programs into 3 classes by risk level, which in turn determines the level of certification and oversight required:


-          Class I: iPS cells, ES cells, other allogeneic cells, gene therapy, other engineered cells and high risk programs

-          Class II: Autologous cell therapies

-          Class III: Autologous cell therapies without transdifferentiation


Programs are further categorized as Medical Care, which are patient pay commercial programs, and Clinical Research. As of this writing, the current total number of RMP programs in Japan is 3,704. Of these, there are 144 registered Clinical Research Programs nationwide.



Medical Care Programs

Clinical Research Programs

Class I



Class II



Class III




The requirements before initiating first-in-human clinical studies include product, CMC and non-clinical study factors. In terms of product factors, the applicant must investigate the main and secondary pharmacological actions in vitro and in vivo and confirm the mechanism of action of the therapy, the characteristics of source cells and the rationale for animal models to be used in non-clinical studies.


CMC requirements include an explanation of the structure and other product characteristics, process for the management of impurities and an explanation of the method of ensuring quality consistency of the investigational product.


Required non-clinical study results include pharmacodynamics, immunological cross-reaction data, in vitro safety pharmacology and toxicity. The minimum anticipated biological effect level (MABEL) needs to be defined based on the results of these non-clinical studies in the most appropriate animal models.


Besides certification and oversight, the Safety Act also includes one accelerating aspect. It enables medical institutions to outsource cell culturing and processing activities to certified companies. This was seen as time consuming and a development bottleneck for some medical facilities.


The current number of approved cell culturing and processing facilities, including medical institutions and companies in Japan is 62 for Class I programs and an enormous 2,510 facilities for Class II and III programs. In addition, the MHLW has approved 5 companies from Korea and 1 company from Taiwan. There is an opportunity for more overseas CDMOs to obtain MHLW certifications under this regulation.


The sheer number of facilities requiring materials, media, systems support and logistics must represent a significant business opportunity, if one is to believe the gold rush adage of profits being made by those supplying the miners.


We see that five years after the new regulations, many companies and medical facilities are active in cell processing and clinical studies, and a robust ecosystem has grown around this clinical and research activity. The initiation of studies has become easier and the possibility for early conditional approval makes Japan particularly attractive.


However, the fact remains that Japan still has only 4 RMP approvals: JACE and JACC from J-TEC (a FujiFilm subsidiary), HeartSheet from Terumo and TEMCELL from JCR Pharma.


So, what does the future hold? It is helpful to look at the IND / Clinical Trial Notification submissions to see what approvals are likely to come soon. It’s also interesting to note the following 3 foreign capital firms with ongoing clinical trials in Japan: Novartis Pharma, Janssen Pharmaceutical and Caladrius Biosciences.



Cell Therapy

Gene Therapy


Sponsor Submissions




Investigator Submissions









Our view is that Japan is an attractive market with many ongoing clinical programs and a significant number of new approvals coming in the near future. Information from the PMDA showing an increase in the number of development consultations for RMPs indicate that the number of clinical research programs and clinical trials will continue to grow.


We are on the cusp of regenerative medicine breakthroughs in Japan, and five years into the new regulatory regime, in many ways it still feels like we are at the starting gate.


Japan enables early initiation of development programs based on supportive regulations, highly motivated researcher physicians and an advanced ecosystem of medical facilities and companies. Japan also offers the possibility for approval based on limited data which can come from physician-initiated studies.


It’s true that there are only 4 approvals so far, and it’s also true that not every RMP program in Japan will utilize the conditional approval pathway available for regenerative medicine. While this pathway enables a quicker route to patient access and commercialization, some companies feel there are drawbacks versus a traditional development path. Those include all-case post-marketing surveillance and limited ability for commercial rollout to a broad number of medical facilities until the full approval is obtained.


Another interesting factor is that Japanese regenerative medicine companies with global reach are not starting all their programs in Japan first as a matter of course. They are certainly focused on Japan development but are choosing their first region for each of their programs based on epidemiology and market needs. Fujifilm and Healios are examples of Japanese companies with overseas RMP programs.


For an overseas company looking at coming to Japan, regardless of whether you intend to develop your asset yourself or license to a Japanese company, and whether you plan to develop based on the conditional approval or traditional pathway or decide along the way, two factors will be absolutely critical to your success. First is selecting and partnering with KOL doctors. Second is collaboration with the PMDA.


Doctor relationships at important facilities are necessary for generating medical society support, political support and validation for your program. Onboarding your investigator team early with a full understanding of their motivations, personal and facility capabilities, relationships and network is of great and lasting importance. Their involvement in Japan can also support your ex-Japan activities and networks.


Positive PMDA collaboration is also necessary for success. Ensuring your Japan-based investigators are fully supportive and willing to advocate in front of regulators is one factor. Another is to remember that RMPs are hard to regulate, and every program is new and unique. Despite the PMDA’s good intentions, they will struggle to regulate and approve new and unfamiliar programs.


Sponsor companies should think of the PMDA as a partner that requires support in order to move programs forward. Partnership and collaboration among the sponsor company, KOL doctors, the PMDA and experienced consultants is necessary for success.


Japan is open for RMP business, and I hope we can help more overseas companies launch their programs here.



Bart Van der Schueren, Ph. D, M.D., The European Regulatory Framework (cont.) …


European regulators rightly understood that harmonization was needed between its 28 (soon to be 27 because of Brexit) member states in terms of the requirements to obtain marketing authorization.  This “one stop” for regulatory approval within the European Economic Area (EEA; i.e., the 28 (soon to be 27) member states of  the European Union (EU), Iceland, Liechtenstein and Norway) has the obvious advantage of saving valuable time that was previously lost because of fragmented requirements and processes in each member state. In addition, it expands access to a much wider expertise available across all countries and a better monitoring of the safety of medicinal products throughout their life cycle.

It was this need for harmonization that led to the founding of the European Medicines Agency (EMA) in 1995 for the protection of public and animal health through the scientific evaluation and supervision of medicines.  The EMA’s Committee for Medicinal Products for Human Use (CHMP) is responsible for conducting the initial assessment of EU-wide marketing authorization applications, assessing modifications or extensions (‘variations’) to an existing marketing authorization, considering recommendations of the Agency's Pharmacovigilance Risk Assessment Committee  (PRAC) on the safety of medicines on the market, and when necessary, recommending European Commission changes to a medicine’s marketing authorization (including its suspension or withdrawal from the market). The centralized procedure is mandatory for human medicines for the treatment of HIV/AIDS, cancer, diabetes, neurodegenerative diseases, auto-immune and other immune dysfunctions and viral diseases. In addition, it is mandatory for all medicines derived from biotechnology processes, advanced therapy and orphan medicines. Potential marketing authorization holders (MAHs) of other medicinal products may opt for a centralized or decentralized procedure in one or more EU member states simultaneously.

Recognizing that his need for harmonization between member states created EMA is a key to better understanding how it differs from the Food and Drug Administration (FDA) in the U.S. The FDA developed as a consumer protection agency and has the advantage of centralization and common rules across the American States. The EU regulates medicinal products through a network of centralized and decentralized agencies throughout its member states and has to strike a difficult balance between harmonization while preserving national autonomy. This affects how marketing authorizations are assessed. Within the European system, two member states are nominated to assess a marketing authorization (rapporteur and co-rapporteur). They independently assess the marketing application in terms of quality, pre-clinical, pharmacokinetic and pharmacodynamic and clinical data until day 80.  Subsequently, their assessment and a list of outstanding issues are presented to all other member states for comments and a consolidated list of outstanding issues precluding marketing authorization is returned to the aspiring MAH.  Its responses are then assessed and discussed at CHMP, until a positive benefit risk balance can be established and CHMP can adopt a positive opinion for marketing authorization.  In addition, the post-approval measures and risk management plan are agreed upon between the PRAC and the aspiring MAH.

The total assessment time amounts to 210 days (or 150 days when accelerated), excluding ‘clock-stops,’ during which the aspiring MAH formulates responses and conducts additional analyses.  Ultimately, the applicant also has the opportunity to defend its position to all EU member states and Norway and Iceland during an oral explanation. The final decision is reached either by consensus or vote in which a majority is defined as 17 of the currently 28 members + 5 co-opted members (individual members of CHMP selected for their expertise). Norway and Iceland can comment, but do not have a vote within the system.

This process is different from what happens under the FDA, where medicines are approved by divisions with jurisdiction over therapeutic areas and modalities, and the agency is more broadly responsible for the safety and security of the food supply, all cosmetics, dietary supplements, health care products that use radiation and medical devices.  In contrast, EMA only regulates medicinal products.

The European attempt to harmonize drug approval has proven to be successful.  It remains however fundamentally different from the system in the US and also does not guarantee that a marketed drug with a demonstrated positive benefit risk will make it to patients.  This is the ultimate challenge in a continent where health care is provided and reimbursed by each individual member state.  There are attempts to improve the collaboration between payers and the regulatory agency.  However, it is easy to understand that this is a challenge in view of the heterogeneity of the financial capability of each member state.  Nonetheless, the European system has clearly demonstrated its value and will continue to do so for member states that opt in.  Brexit confronts EMA with the challenge of moving from London to Amsterdam and losing one of its most valuable members.  However, it is ultimately a spirit of cooperation that will ensure Europeans to have access to the best and most innovative medicinal products.  Honi soit qui mal y pense.


The views expressed by the author are his personal views and may not be understood or quoted as being made on behalf of or reflecting the position of European Medicines Agency (EMA) or one of its committees or working parties.




Lana Pauls, MPH, My Career Continuum (cont.) …

The Beginning:

I started my career at the FDA in 1990 as a Project Manager, interestingly enough, working from time to time directly with Kinexum founder, Dr. Zan Fleming, for approximately 6 years (I stayed in touch with Zan until he left the Agency in mid-1998).  One of my most memorable experiences as a project manager was when a Medical Officer in the review division told the sponsor that they had to re-do a $1.7 million trial because she “didn’t like the design.”  This happened in my first week on the job, and I was simply awestruck.  At this point, from a sponsor’s perspective (and mine), working with the Agency seemed like navigating a black hole, as there was no ‘true’ project management, and absolutely NO transparency or consistency across the review divisions.   The sponsor heeded the advice and repeated the trial.  This made me think the Agency had omnipotent powers.

With the implementation of the original Prescription Drug User Fee Act (PDUFA) in 1992, project management was institutionalized, and processes, procedures and communications slowly began to improve.  PDUFA also increased funding, and established timelines for reviews.  In approximately 1999, the Center for Drug Evaluation and Research (CDER) implemented a Quality Assurance (QA) unit to help increase consistency and transparency. 

PDUFA II to PDUFA VI continued to implement increasing consistency and transparency, by mandating new timelines, development of guidances, pilot programs, and public meetings.

Over the years, I held a variety of leadership roles in project management, quality assurance, strategic planning and training, and observed the Agency evolve from an omnipotent regulator to a supportive regulator giving tractable guidance to the pharmaceutical industry.  I cannot deny that there is still a sense of mystery from the sponsor’s perspective, especially for start-up pharmaceutical companies.  However, my perspective certainly changed over the years, and I now truly believe that the FDA and Pharma are “on the same side” in terms of delivering safe and effective life science products to patients.

The Next Step:

After 26 years at the FDA, culminating in a leadership position in Post Marketing, I joined IQVIA (formerly known as QuintilesIMS) as a Director of Global Regulatory Affairs (GRA), in which role I provided regulatory affairs strategies and supported regulatory CTD submissions to the FDA and other regulatory authorities.

IQVIA, with over 59,000 employees is the largest Contract Research Organization (CRO) in the world.

When I moved to IQVIA, I thought that the mystery would diminish because of the volume of “working knowledge” and established SOPs.  Although hundreds of SOPs were in place for the vast number of employees on payroll (I was required to sign off on over 70 SOPs in my first week), the actual day-to-day work was not necessarily well-defined, and often inconsistent across individuals on the same team, as well as across project teams.  This “industrialized approach” and multiple silos (each having its own “piece of the pie” sometimes interfered with morale, and could lead to differing interpretations of regulations, causing inconsistencies in final work product and delays.  In addition, GRA was not centralized, and existed as a sub-group among multiple Operating Divisions, which again contributed to inconsistencies and sometimes confusion.  This experience impacted my perspective of how a large CRO views FDA’s opinions and comments and its relationships with current and potential clients.

Current State:

After two years with the large CRO, I decided to work either within a smaller company, or as an independent consultant.  I have found a productive and enjoyable application of my expertise and experience in consulting for Kinexum clients, helping Kinexum implement systems and processes and engage with its clients, and conducting assignments through my Regexel, LLC.  I have great respect for my Kinexum colleagues, who are dedicated and collegial professionals, and see the value for clients of the Kinexum approach, which can assemble a team of experienced functional experts to advise regarding the complex, interdisciplinary work of life science product development.


The common bottom line throughout my career has been the motivation to more effectively and speedily bring safe and effective products that save lives and improve the quality of life for the American public, and this has brought, and continues to bring me, deep satisfaction.


Upcoming Conferences




Upcoming Webcasts

“European Medicine Agency – Some Recent & Anticipated Changes”

Presenter: Dr. Bart Van der Schueren, IG Endocrinoligie UZ Leuzen, Belgian Representative on EMA

Date:  Friday, July 13, 2018

 Time:  11 a.m. to Noon, EDT

Click here for log-in and call in information 



New Kinexum team Members

David Brill, Ph. D

Regulatory Affairs

To learn more about David

Jennifer Zhao

Kinexum Associate

To learn more about Jennifer


Kinexum provides strategic regulatory, clinical and non-clinical, manufacturing and other translational advisory services for life science product development.

Our experts typically have decades of experience in government, industry and/or academia, and have broad experience with a range of modalities (including small and large molecules, devices and digital health) and therapeutic areas (including diabetes, cardiovascular, GI, oncology, neurology, wound healing and infectious diseases). We manage and salvage complex assignments, and file regulatory submissions and negotiate with the FDA and agencies in other major markets.

If you would like to learn more about how Kinexum can help you, please contact us at: This email address is being protected from spambots. You need JavaScript enabled to view it. , Kinexum Services LLCPO Box 1260, 550 East Ridge Street, Harpers Ferry, WV 25425, (p) +1 (304) 535-3037, (f) +1 (304) 535-3166,  www.Kinexum,com.Follow us on Outlook Logo LinkedIn

To unsubscribe please email This email address is being protected from spambots. You need JavaScript enabled to view it.