A brief history of the launch of one (the first?) Anti-TNF agent Ex-US

Over the last couple of weeks, I have been affected by a cold, or flu, plus an ear infection and left me miserable at home with lots of time to watch TV. Not the most educational activity but when you can’t concentrate, the remote control and empty programs help. I did notice the huge amount of commercials for Humira and other biologic agents and recalled many issues by focusing on the “small fonts” or “fast fair balance messages”.

I was there when Remicade was launched outside of the United States. I wasn’t actually the first “product manager”, that role fell on the extremely talented Margaret (Linguri) Dean, now at Novartis. She was the first one and I just came after the initial launch for Crohn’s disease.

At the time, nobody in the company (Schering-Plough) cared for Remicade, despite Margaret’s heroic efforts, and most people didn’t think it would ever result in a blockbuster drug. As a former boss and friend once asked me: “Why do you want to work on that drug? It will never sell much, it is an infusion, it will cause lymphomas, and sales will disappear once subcutaneous drugs become available…” I was sure he was wrong, but I hope to communicate many of the issues we had to deal with in the early days through a few vignettes. This is not intended as a complete history or to have these vignettes in the perfect timeline, but I chose them because I think they are the most relevant to the current situation. And because of the passage of time, I may recall some issues with a degree of bias, the order may not be totally accurate and some names may have escaped me. I apologize in advance for this. If anyone wants to know more, just contact me.

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One of the first things I noticed when I started working was that sales were actually sluggish despite the enormous interest from physicians in all countries. I couldn’t understand why things were working the way they were when most doctors appeared so enthusiastic. By chance, once I went to work on the field with sales representatives in Europe to check the on the ground situation. Most use of Remicade was only allowed in hospitals, so being in the field meant visiting tons of hospitals all over the continent. The sales reps would take me to see the doctors and rarely, they would take me to see the hospital pharmacist. At one point, I had the crazy idea to ask the rep to show me the infusion chair or suite for Remicade. I was replied with stunned silence. “Not my responsibility”.  It occurred to me immediately that the “concept” of the product by the field only included until the point where there was inventory in the pharmacy.  The product was “sold”. I expanded this to include the infusion. I started asking all the countries to send me pictures of the infusion chairs, suites, etc. I encouraged them to develop their own plans, based on their legal and regulatory situation to make sure that infusion centers were easily available, convenient and welcoming to the patients. The message changed to “Remicade is not sold until it is being infused”.  Every country had a different way to implement this. From Global, I couldn’t care less what approach they used as long as it complied with the local regulations and satisfied the customers. Eventually, they had to “improve” them so it became a positive differentiator against subcutaneous drugs. Probably, the most original program was implemented by Bruno Mader in Canada. He was incredibly innovative and with dogged competitiveness. He wanted to win and to this day, Canada has the best infusion logistics of any country. In the beginning, the issues in most countries were chaotic. I remember visiting an infusion center in Barcelona that shared the space with the “birthing” room. You had chairs with patients getting infusions, and in other chairs you had women in labor with their partners holding their hands. All very surreal! This had to be the most different way to look at access issues. But once everyone understood this, the solutions came quite quickly. I don’t think that nowadays any company with an infused biologic has even considered the logistical situation.

I should clarify that hospitals in the EU DID have infusion units But most of them were in Oncology departments. patients with Crohn's disease, and later those with rheumatoid arthritis, did not want their infusions in the Oncology units.

The situation in the United States was very different as the doctors were allowed to get somewhat generous reimbursement for conducting the infusion in private practices, so this need was not that apparent. In the EU, the infusion fee was minimal and only allowed in hospital. 

Another big issue that seemed to happen a lot during the early years had to do with the “appearance” of serious adverse events. Probably, the most serious one was the appearance of cases of reactivation of tuberculosis. This was truly a very difficult matter to resolve. I recall that the Chief Medical Officer of the company and the co-lead of the Remicade team was Dr. Robert “Bob” Spiegel, with whom I had the most productive and fun experience. Bob is brilliant and he is one physician that understands the clinical aspects and the business impact. He is not a “commercial” guy/doctor, he is a true business man. We would switch roles for discussion to understand the other’s point of view, but many times, his business view was the superior one. He called me one day to tell me that cases of TB reactivation were popping up with increasing frequency and that Centocor, the drug’s developer, was very concerned and was even considering removing the drug from the marketplace. A “safety” meeting was being organized in haste with a huge staff from both companies. Bob and I realized that unless we had “external” views of the drug, the meeting could end up in disaster. We reached to Dr. Scott Plevy who was then at UNC, Chapel Hill. Scott was marvelous and was able to convince everyone of the clinical value of the drug and the absolute need in the marketplace. I am convinced he “saved” Remicade that day. But the second issue to resolve once it was determined we wanted to keep the drug in the market was how to convince the European Regulatory authorities that the TB issue could be managed. Bob and I relied on another important person in the group, Anthony “Tony” Angiuoli of regulatory. We developed a plan where we were going to educate all European (and international, but I will stay in the EU for now) Remicade prescribers of the steps necessary to screen patients for TB. We had the incidence rate of reactivations before the program, and Jeff Ho (from Market  Research) worked to develop a questionnaire that would be implemented every six months with target awareness numbers of the screening tools. The sales forces communicated the need, and Jeff worked with Tony to track the efforts and report to the EU authorities. The work was very well received and I have to think that it is a good reason we still have these drugs with the “safety” message in the commercials. By the way, the incidence rate declined significantly after the sales activities demonstrating the value of the screening tools, especially when the actions were tracked. Every physician prescriber is aware of these risks today. There were other safety scares, but TB was the classic one that required a very special response.

When the indication for rheumatoid arthritis was approved, a very big internal issue arose. The Key Opinion Leaders were telling us of the significant need for the drug in the marketplace. The epidemiologic data was also very strong and in Global we were expecting big revenue potential. But the subsidiaries had conducted their market research that suggested sales were going to be minimal. The classic conflict between the head office and the people in the field! The President for European Operations was Roch Doliveux, who much later became CEO of UCB in Belgium. I remember Roch asking me why he should trust my figures and not the ones from “his” people in the field, closest to the business.  This needed a creative solution. It was true that physicians with limited trial exposure to Remicade perceived that patients were well treated and only few needed additional care. So, with the KOLs we designed a patient and physician survey. Using properly validated tools, patients would answer questions regarding their care and physicians, blinded to the patient’s responses, would provide their assessments. This was done almost completely externally to the company. The University of Erlangen managed the project. The reps jobs, after fulfilling local regulatory and compliance criteria, had to deliver the surveys and then pick up the sealed envelopes once completed. Over 6,000 patients participated over one day only. By Global staying at arm’s length and having the field implement it while the analysis was being done by a well regarded center, we gained immediate credibility with all parties: The field, senior management, the KOLs, the prescribing physicians. The only possible “loss” was if the results would not sustain the need. COPQOL was the name of the study. It was presented in a few congresses but for reasons that I will not divulge here, the manuscript was not published. But the results were amazing. The market potential was very close to the epidemiologic data. And for the prescribers it showed that patients were very unsatisfied with their treatment. There was a huge discrepancy between what the doctor thought about the patient and what the patient was expecting. Even savvy KOLs were very impressed! Senior management then had the tool to convince the countries to invest and they knew that the potential of the drug was immense. Global won! 

These are just three examples of the issues going on at launch and during the first years of the drug in the marketplace. There were others that may not appear that dramatic but also had significant influence.

One important aspect for Remicade had to do with the generation of clinical data that would continue supporting the drug. It may not be well known, but all (or probably most) of the indications for Remicade resulted form external proposals, or Investigator Initiated Trials. Remicade was actually championed by Sir Ravinder “Tiny” Maini and Marc Feldmann of the Kennedy Institute of Rheumatology in London. Tiny and Marc generated the pre-clinical data, designed the studies and convinced Centocor to provide them the drug. It was even a random discussion with Sander Vandeventer where the idea for the study in Crohn’s disease occurred. Tiny and Sander shared a taxi to Centocor in the US and discussed the possible research.  The ankylosing spondilytis study was another IIS by Dr. Jürgen Braun from Berlin. Almost all the studies were heavily driven by outside experts! Internally, I was very lucky to work with people like Fran?ois Lafleur and Vanessa Thirion-Cullity who helped tremendously in managing those efforts. Now, most companies have a very silo approach to medical affairs, but at that time, there was excellent communications between the groups. There are many studies that are very popular that came from the support from Fran?ois and Vanessa (BEST, Step-up/Step down, as two examples). But, outside experts had a very open communications with me and with any other member of the team. I have to recognize Tiny Maini and Paul Rutgeerts as my godfathers in these fields. There are many KOLs still in practice that have been wonderful, but I prefer to keep their names private for now. They remain good friends and advisors.

These vignettes only show the activities or issues from the "Global" perspective They do not want to minimize the efforts and thinking provided by the countries. In all these instances, the implementation was by the countries and our role was to drive the processes. As usual, in some cases the relationships were tough and in others they were extremely productive and friendly. In some instances, it wasn't the teams in the countries that were "hard" but they had to deal with incredibly creative limitations driven from the governments. I am most grateful to all the people I worked with from the subsidiaries.

I presume that for many people, these vignettes will appear as quaint. But they were huge issues at the time. They required an enormous amount of creativity, teamwork, patience, innovation and ability to execute with limited resources and experience. We were creating what didn’t exist; there was no launch map of mAbs at the time. I am grateful to all the people I worked with at the time. I mentioned here the “internal” members but there were many at Centocor that were great team players too. I do want to mention Richard Melsheimer, Freddy Cornillie and Mark Fraga (plus many names that escape from my mind, I am so sorry!) as the ones that generated the most trust and respect and remain friends.

I have had experience with monoclonal antibodies for over 20 years now. Many of these lessons and insights are still relevant.  I am fully aware of issues between the home office and the field. Get in touch if you want to discuss your issues and how I can help you now.