Opening Lecture ECTRIMS 2003, Milan, September 17
Prof. Otto R. Hommes

I would like to thank ECTRIMS for the invitation to give the 2003 ECTRIMS Lecture. It is a great honour for me.

My presentation carries as a title

Quo vadis? Where are you going?

and is directed to all those concerned with MS research in Europe especially, but also to a wider audience. A subtitle of Quo vadis is

Agenda for European MS Research

and I will spend the coming minutes to discuss with you some questions on the organization of clinical MS Research in Europe.

Scientific progress has a political aspect. It is reflected in societies’ willingness to direct attention and funds to specific fields of research.
Political pressure can be generated by catastrophic events and/or by organizations if these organizations express their interests succinctly, clearly and constantly at the highest political levels.
Recent examples in medical research and health care are the campaigns to eradicate poliomyelitis and HIV, and clearly SARS is a good example.

Clinical MS Research, as a part of neurological research has in Europe remained at a lower step of the organizational ladder. In Europe the national winds still prevail, and although a few European MS Research organizations exist, they have as yet no power.

An opportunity to improve this situation presented itself when the European Neurological Society (a society of individual neurologists) and the European Federation of Neurological Societies started discussion on co-operation in 2000 and 2001. However, the first common objective: a Joint European Neurological meeting in 2006 was rejected in 2002. A missed opportunity.
And maybe it is better not to start with an elephants wedding, but with bringing much smaller animals of the European Neurological Zoo together.

For Multiple Sclerosis, two organizations exist that may be described as MS Research Organizations:

Let me concentrate on these two organizations and ask "Quo vadis?”: where are you going? This 19th ECTRIMS Congress in Milano is in my opinion an excellent forum and a good opportunity to discuss the agenda’s of ECTRIMS and the European Charcot Foundation, and in general the agenda of European MS Research; not in the least as a mark of respect for this city, for the San Raffaele Hospital and its excellent MS Research Department under the leadership of Prof. Giancarlo Comi, our host.

Of course I give here my personal opinion, as it comes from someone with longstanding experience as well in ECTRIMS as in the European Charcot Foundation.

I sincerely hope that you as an audience, as MS Researchers and those strongly interested in treatment of MS, that you might be willing to follow me in some peregrinations in that field: on what has to be done on the organizational level in European Clinical MS Research:
Agenda, I said, are those things that have to be done, are in need to be done, things that cannot wait. In the course of my presentation I hope to make clear to you why some things cannot wait longer. In doing so I will not cede to the temptation to discuss specific research items, as we see them emerging in neuronal loss and its prevention, MRI aspects, new treatments. No, I want to do more.

Sixteen centuries ago this city -Milano- offered a professorship to a brilliant teacher and freethinking philosopher, to St. Augustine- as we know him now. Here in this city, under influence of Bishop St. Ambrose, he renounced all his unorthodox beliefs, converted to Christianity and was baptised in 387.
This is historical, maybe sacred ground; on which I will try to convince you, better convert you. You as the brilliant freethinking scientists, me as a sort of St. Ambrose trying to convert you to the European dimension of clinical MS Research.

This may be a difficult undertaking because discussing new organizational structures implicitly means that existing structures are insufficient. And indeed: this is my opinion. Therefore: in discussing the organizational agenda for European clinical MS Research at the Milano ECTRIMS Congress, I pray for help to the god of distant travelling, commerce and secrecy (Hermes) to bring this endeavour to a good end. And of course a prayer goes to Asklepios. Both gods know Milano well.

As I said there are two European MS Research Organizations.
ECTRIMS is a democratic organization, with national representatives, who elect an Executive Committee with restricted tenure. ECTRIMS’ corporate status is unclear. Its main activity is the organization of very successful annual congresses. This activity is ceded to a local organizing committee. The financial structure of ECTRIMS is unclear. The organizational goals, other than the yearly congress, are vague. ECTRIMS does not have a central bureau facility, its political influence is underdeveloped but has great potentials. ECTRIMS contributions to the awareness of MS in Europe has been, and is invaluable. The Milano Congress again testifies this.

To qualify as a real MS Research Organization ECTRIMS should add to its activities:
High level leadership on supra-national levels in the fields of drug-development and registration, teaching and recruitment of young researchers, funding, data basing, and most of all a supra-national guidance in clinical trialing. A well-equipped standing bureau is absolutely necessary.

The European Charcot Foundation is a Foundation registered at the Chamber of Commerce in Nijmegen, the Netherlands. It is governed by a co-opted Board of 17 recognised active MS Researchers. It is a non-profit, independent foundation for the enhancement of MS Research in Europe, sponsored by private organizations, MS Societies and Industry.
The Foundation has a standing bureau under the managing direction of Mrs. Friedrichs Bosmans. The Chairman and the bureau are supported by a 4 member executive board for daily governance.
The Foundation’s activities are the yearly organization of specific symposia and satellite symposia, teaching courses, treatment trials (ETOMS, ESIMS, GAMPP), publications. The Foundation’s budget is small, its political influence restricted.
In its stable corporate structure, its bureau, its activities and goals, the European Charcot Foundation is complementary to ECTRIMS.

Asking the same questions we posed to ECTRIMS on its qualifying for a research organization, I think the European Charcot comes somewhat closer, but in a modest way.

I will discuss four points to underscore my position
1. A European MS Research Organization could bring leadership and stability. Caption: leadership.
2. It could formulate multi-annual research priorities and goals. Caption: goals.
3. In co-operation with authorities and pharma-industry, budgets and funds could be secured. Caption: funds.
4. A far higher level of political representation at EU governmental level by lobbies and pressure groups could strongly enhance scientific progress in this field. Caption: political competence.

• leadership
• goals
• funds
• political competence

And I will end my discussion with some words on a larger Europe and the younger generation of investigators.

Leadership
Leadership for MS Research in Europe should be the prime task of a European MS Research Organization. The leadership should envisage common goals, goals that should be clear, simple and constant over a longer period of time, and that should be scientifically, politically and ethically convincing.

• Leadership should
• represent European Clinical MS Researchers
• formulate common European research goals
• oversee good clinical practice in MS research
• create high educational and ethical standards
• its political and scientific influence should reach;
  • European Centres of clinical MS Research
  • registration authorities EMEA
  • European Union Parliament and Council
  • educational authorities in international scientific organizations ENS, EFNS, WFN, European MS Platform
  • publishers
  • pharma-industry
  • European National MS research organizations

But leadership is not only a question of organization. It is also, maybe mainly, a question of persons, of personal abilities, of creative dedication to a common goal. Such leadership takes time, much time. My estimate for the chair of a large European MS Research Organization would be that it is a full time position.
Of course the person chairing such an organization should be experienced and highly regarded in the field of MS Research. With such a background she or he will open doors and advance plans that would fail in the hands of pure managers.
And because this person and her/his bureau have to be well paid to resist the temptations of other positions, funds are needed.

It should be stated clearly: key functions in a European Clinical MS Research Organization should not be voluntary or honorary positions.
I am sure that such a person can be found under the large number of highly respected European MS Researchers. She or he should take this position for at least five years and the bureau of the European MS Research Organization should be part of her/his office.

As the situation stands now, most treatment trials are initiated and funded by industry that claims full ownership and control of trial data. And such occurs in a time that patient populations available for treatment trials are reduced because licensed treatments are available.

Under leadership of a European MS Research Organization, representing clinical MS investigators, this situation could be changed in several ways.
Choice of research options, trial conditions, planning and data collection should be under full responsibility and control of investigators. The question of intellectual property should be cleared.
In such a way a European MS Research Organization could be in a position to improve and guarantee the status of MS clinical trialing in Europe.

Investigator driven trials should become the normal situation, instead of being a sort of surrogate for the large well-funded pharma-controlled trials of the last 15 years.
But this would mean a complete change in responsibility, in knowledge and in execution of clinical trials.
And –another important consequence- those who generate the data should be the owners of these data. In such a situation the relation between investigators and pharma-industry will be fully different from what is normal now. Such a change can only be realized through the existence of a European Organization of MS Investigators.

Let me first concentrate on an aspect of crucial importance: the formulation of research priorities. To indicate what I mean here I will give an example.
In MS clinical trialing there are several questions that should be solved as quickly as possible. Giving priorities would say: as soon as we have solved the most urgent and important one, we will tackle the other.

Here the two urgent questions:

1. Appearance of neutralizing antibodies against IFBs. Extrapolating a recent Italian study, neutralizing antibodies might seriously hamper the bio-availability after 4 or 5 years of treatment reducing treatment effects.
2. The auto-immune genesis of MS is more and more in doubt now that many studies have indicated early axonal loss even without cellular infiltration. As investigators from this city have recently shown, this happens already at the earliest stages of the disease. The answer to the question what causes this axonal damage at such an early stage has immediate therapeutic consequences, and should be solved as soon as possible.

Given restricted funds and investigator capacities, only a European MS Research Organization, carried by investigators could make the choice here.

A European MS Research Organization. Why now?
In general the European countries have not been successful in raising levels of scientific development and innovation in recent years.
Figures indicate that there is a steady decline in the 15 years between 1985 and 1999 for Europe as a whole and for countries separate.

In 2002 the percentage of BNP spent on research for Japan was 2.9 and for the USA 2.6. For Europe 1.9%. At the Barcelona 2001 summit the EU decided to raise that figure to 3% by 2010, but it is common knowledge that this will not happen.

For the 2002-2006 cadre programme the EU will spent 17.5 billion € on scientific development. 2.2 billion (12%) is for Life Sciences, mainly for genome, cancer and HIV research.

Estimating the prevalence of MS in Europe at 100 per 100.000: MS research could claim 1/1000 of this 2.2 billion: 2.2 million €. But because a focussed approach is lacking, I doubt that even this small amount of EU money will reach European MS research.

The EU Commissioner Busquin is realizing that important research aspects remain out of the scope of the EU. He is now organizing European networks of research excellence around a common programme that will receive higher levels of funding in the cadre programme.

This is exactly the situation for MS research in Europe now. Therefore at this favourable point in time, a European MS research organization should be there to compete for these high levels of funding. And of course the goals should be set wider than EU funds and should explicitly go for active fund-raising, donations and other forms of funding, of which co-operation with pharma-industry is probably the most crucial.
And therefore: maybe an even more important aspect of the task of a European MS Research Organization would be this co-operation with pharmaceutical industries.

Co-operation with pharma-industry
At the present time the relations between the medical profession and industry are under close scrutiny, because some financial and economic ties between the two could seriously hamper independent research.
In a recent Lancet report was stated that in a major European Faculty of Health Sciences, more than half of the researchers have worked with industry in the year 2001. One of the most common relationship was involvement in a project co-financed by university and companies. A review of the situation indicated that balanced share between government and company financing was found in Denmark, Norway, Finland and Germany. Low government funding (and high company funding) was found in the USA, Japan, and Sweden. The reverse: high government funding in Italy, Mexico and Turkey. In this review concerns were voiced that government funded research was being side-lined for better-paid commercial work.
There is a tendency now to change the financial ties between research and pharma-industry. It would be wise not do disrupt but to improve them.
For MS research the pharma-industry has been of utmost importance. Recent development in clinical trialing and their therapeutic results were strongly enhanced by the commercial interest of the pharma-industry.

That these companies are interested in returns on their huge investments is sound commerce. However, investigators’ and patients’ interests should be as strongly defended as the companies’ interest. Intellectual property, protocol structure, ownership of data, rights to publications and post-marketing follow-ups are aspects that have to be strongly improved, and brought under investigators responsibility.

Investigator controlled trials
A far more important place should be given to what is now called "investigator driven trials”. In my opinion only a European MS Research Organization could upgrade such new developments in a way that he who produces and owns the data will receive revenues from it. I touch here on a taboo that however should be widely discussed again in the light of recent reduction of pharma-funding in new drug developments.
It is the question:

"Why should an investigator in clinical trials not have financial benefits from the results of his trial?”

or to formulate it in a positive sense:

"A clinical investigator should financially benefit from the results of his drug research work.”

I do not mean here that he is reimbursed by a pharmaceutical company. What I am aiming at is that the investigator, his department, his institute, his university should receive continued financial revenues from the marketing of a new drug, developed and studied by him. The principle should be that the revenues from drug research should also go to those that provide the data of its effectiveness through clinical trials, and not only to the producers of the substance. The investigator can, through the high standards of his work and his institute, guarantee the conclusions drawn from his data and so provide very important marketing arguments.

Just to enliven this discussion with an up-to-date example the following: according to a recent article in Le Monde (August 20th 2003) Astra-Zeneca will spend 1 billion dollars on the marketing launch in the USA of its new anti-cholesterol. This amount of money will be represented in the price of the product. The investigators, who proved the effectiveness of the drug, will not benefit here. If the investigators would own the data, benefits of marketing of the drug should also return to the investigators. Of course the investigators should be fully independent of the drug company, and this fully independent position would guarantee the results. The investigators should carry full responsibility for all details of the clinical trial, should set the highest standards for protocols and data collection, handling and publication.

Under these circumstances benefit sharing should lift investigator controlled trials to the highest standards of independence, reliability and ethics. And by its revenues could guarantee continued funding of essential clinical trials.

CROs
It is impossible to avoid discussing the position of modern clinical research organizations: the CROs. As you will have noticed, I hold the opinion that many tasks of modern CROs should be under full investigators responsibility. The present day position is that pharma-industry has developed its own CRO activities, or contractually hires CRO know-how from larger or smaller CROs. Clearly the investigators’ position in relation to heavy weight pharma and CRO combinations is weak, not only because the others are well organized and powerful, but certainly also because investigators do not have a powerful organization to present them as respected partners in discussions.

I will even venture the proposal that clinical investigators should set up their own CROs, and in this way will have full control of protocol development, execution, standard operation procedures, personnel and finances.
In this way, CROs should be academized. Only a European MS Clinical Research Organization could be in a position of strength and power to realize this.

Clinical trialing: a new science
But such a movement could also be envisaged for the pharma-industry, to realize a high-level co-operation, beneficial for both sides. The immense know-how, data bases, specific information that are now hidden and will probably remain hidden in archives of pharmaceutical industries, should become available.
Clinical Research and Development has become a science of its own, and this new science should be introduced to our teaching institutes as soon as possible. Those pharma-industries that have contributed so much in recent years to MS treatment research (and have gained a lot), should establish MS Clinical Research Chairs at main MS Research Institutes. These chairs should be lavishly funded to create independent clinical treatment research. And this all of course guided by and under the auspices of a European MS Research Organization.

MS Expertise in Europe is high, and a number of excellent MS Clinical Research Centers have been developed over the last 15 years: showing that MS Research in Europe is vigorous and strong.

It now should gear into the next phase in which full co-operation between these centres will be the pushing power for a European MS Research Organization. The ECTRIMS Executive has in his hands a proposal from the European Charcot Foundation that goes in that direction, and you will understand that the European Charcot Foundation is expecting a quick and positive answer here.

From this point of view the presence of the Sylvia Lawry Center for MS Research in Munich under the umbrella of the MS International Federation is an asset that should further stimulate the start of a European MS Research Organization. In co-operation with the Sylvia Lawry Center, the stature of the European MS Research Organization towards EU, regulating and funding authorities will be enhanced.

MS Clinical trialing in the "old-fashioned” way will become more and more difficult, with the advent of treatment of early stages of the disease. Recruitment of placebo patients may become very difficult, if not impossible from an ethical point of view. New trial designs, new primary end-points, new roles of MRI techniques, and new parameters for disease type, severity and course, have to be developed.

Europe
Europe breathes, to cite Pope John-Paul, through two lungs, east and west. Clearly an enormous research potential is available in the Eastern lung and it is absolutely necessary to bring this into a European Clinical MS Research Organization. It is not the question: when? The answer is already there: now! Maybe this is, apart from all other urgent matters, the most important answer to my earlier question: A European MS Research Organization. Why now?

Young MS investigators
This exhortation brings me to the final part of my remarks: young MS Researchers.
The existence of a highly respected MS Research Organization will attract gifted young investigators. In my experience, after a promising start, further developments of many young investigators does not continue because the European dimension of MS Research is not well organized.

I have seen promising young MS investigators switch to other fields of medicine because information on European MS Research and clinical positions is nearly absent. The activities of the European Charcot Foundation are exemplary but far below what is really needed.
The younger generation of clinical investigators may sense the future best, and may have a better function to register great changes at an early point in time.

With this in mind, I come back to the caveat at the beginning with regard to the formation of larger organizations. Maybe younger generations will mistrust these larger organizations and are more interested in small, national, institutional and very specialized groups that have a "face”, are easily approachable, work quickly and have a far more human character.

It would mean that all my remarks on the organization of clinical MS research in Europe may find different answers than suggested here. But one thing will remain: Europe is growing together. This is a process of growth. To cite the late German Chancellor and Nobel Laureate Willy Brandt: "Let grow together what belongs together”. This is the most urgent agenda for European clinical MS research.

The questions posed during this lecture are directed to you as a strongly interested and involved audience. It would be important for me to know whether I could convince you by arguments that such a European MS Clinical Research Organization should be started now. You would do me a great favour if you would send your remarks to the bureau of the European Charcot Foundation. If through your reactions things would move forward quickly in the sense I indicated, for me that would mean the greatest honour to this lecture.