By NextLevel Life Sciences - July 12, 2018

Leading up to NextLevel Life Science’s 10th Edition MedAffairs Leaders Forum Europe (Autumn) 2018, we are conducting interviews with selected members of our prestigious speaker panel to learn more about their thoughts on this vital issue.
*Opinions below are those only of the individual and do not reflect upon corporate strategy or positioning.

For more information regarding NextLevel Life Science’s 10th Edition MedAffairs Leaders Forum Europe (Autumn) 2018 click here!

Kieran Breen, Member of the Committee for Advanced Therapies (CAT), EMA

NextLevel: How would you describe the work that you do on the European Medicines Agency’s (EMA’s) Committee for Advanced Therapies (CAT)?

KB: The role of the CAT is to assess applications for marketing authorizations for “advanced therapy medicinal products” (ATMPs). There are three classes of ATMPs: cell therapy, gene therapy, and tissue-engineered products. It is also possible to have a combination of these. This is an emerging class of therapeutic agents that is undergoing rapid evolution and development and they are at the cutting edge of science. Each of the products is very different in how they are composed and the therapeutic uses that they would be put to. At the moment, nine ATMPs have been approved for clinical use, although others have been turned down. There are four more currently under evaluation. There is a trend for ATMPs to be used for the treatment of orphan diseases, particularly those with a genetic basis, for which there are relatively few patients. Therefore, the products themselves can be quite expensive and this can provide a barrier for their availability.

At the CAT, we assess ATMPs using the same criteria as for any other drug product. We evaluate clinical efficacy in addition to safety, and then we consider the overall benefit-risk ratio of the product, “Is it effective? Will it have a clinical benefit? What are the risks and the potential side effects for the patients?” Based on that benefit-risk ratio we can make a recommendation as to whether the product should be given marketing authorization.

It is also possible that the product can be given partial (conditional) marketing authorization. This is where the company would have to carry out additional studies in order to obtain further data on the drug’s efficacy or safety. We give a conditional marketing authorization when there is an unmet need for the product but we feel that we need more evidence for the longer term use of the product. Once this has been submitted, the product can be considered for full marketing authorisation.

We have recently seen a significant increase in the number of products coming through the CAT which reflects the increased development of ATMPs. One area of interest is chimeric antigen receptor (CAR) T cells. These are designed primarily for the treatment of cancer. We have a number in the pipeline at the moment that are being assessed and two have recently been recommended for approval to the European Commission  – Yescarta and Kymriah – which will be used to treat blood cancers.

The CAT also provides scientific support to companies which are developing new products. Rather than having a company come to us with a marketing authorisation application (MAA) that has significant gaps in their portfolio, we suggest that they come to the EMA at an early stage to ask, “This is what we plan to do. Do you think this is correct?” We can provide non-binding scientific advice for them and it is not unusual for a company to engage with us on more than one occasion as the product goes through the development process. The provision of scientific advice is not unique for ATMPs but is also available for other drugs products. However, because of their unique nature, it may be more important for ATMPs because of the expertise that is available on the CAT and at EMA.

The CAT also plays a key role in the Priority Medicines (PRIME) scheme which allows a product to be assessed in a shorter time-period. To be accepted for PRIME, a medicine has to show its potential to benefit patients with unmet medical needs based on early clinical data. Products are assessed by a panel, with advice from the CAT, to determine whether they are suitable for the PRIME scheme. If so, they are assigned a CAT rapporteur (assessment member) at an early stage who will provide advice and guidance throughout the development process and thus brings them through the system faster. It is important to emphasise that the measures against which the drugs are ultimately assessed (benefit-risk ratio) are the same. So just because something comes through the PRIME scheme doesn’t mean the drug is assessed according to different criteria, nor does it exclude the possibility that it can ultimately be rejected.

The CAT itself is made up of representatives from each of the EU Member States, plus Norway and Iceland. There are also two representatives who have been nominated by patient organizations - I am one of those - and two nominated by clinical organizations. My role is to consider the patient’s perspective, including questions such as “Would this drug be considered effective by a patient? Are we assessing the right factors when we consider benefit-risk?” Each of the member states are representing their own countries. I am representing patients, and the clinicians are representing healthcare professionals, and we all work together towards a consensus opinion. However, if you are going to play an active role on the Committee, one needs an in depth knowledge of the underlying areas of science including genetics and cell biology. This ensures that I can represent the interests of patients based on a sound scientific foundation, while also having an active interaction with patient groups. So, that’s the role of the CAT.

NextLevel: What is the main challenge for implementing and utilising clinical registries?

KB: The background to the use of registries, which is generally agreed throughout the sector, is that there is a lot of patient information out there sitting particularly in silos, in clinics and with individual clinicians, which could tell us a lot about diseases and their trajectory, but they are not being used to their full potential. Several initiatives have been taken to try and overcome this, to aggregate this data, and to develop a big data approach to the development of drugs. One of the main challenges is the differing quality of the data in individual datasets because this can be quite varied.

At the EMA, a cross-committee working group was set up a couple of years ago. I represent the CAT because I have expertise in the use of patient data and the development of registries. I also represent patient organisations, so I really wear two hats.  There are also representatives from all of the other committees as well as EMA staff members who work primarily in the pharmacovigilance area. Our role was to investigate how we could make the best use of the existing data to help us plan clinical trials, and to develop post-authorization safety and efficacy studies. We assessed a number of existing registries and asked, “Would these be suitable to inform us either in the development and planning of clinical trials, or in the follow-up after marketing authorization?” Some of these have now been brought forward we are talking to the people or the organizations who are custodians of the data or the registry and working with them to determine how we can make maximal use of the data. Two that we have done were cystic fibrosis and multiple sclerosis which were qualified at the meetings last year.

We have also been working with the European Society for Blood and Marrow Transplantation (EBMT) which collects data from people who have had bone marrow transplants. We are looking at that to see how we can use that to inform CAR T cell therapies.

So, it’s about trying to see how we can make use of all this information, because at the pre-authorization, and especially clinical trial stages, if you have orphan conditions, it might not be possible to have a controlled RCT. If there are only fifty people with the disease in the country, then a trial becomes rather challenging to set up. We can therefore potentially use data for control patients obtained from existing registries. That’s one way we can make optimal use of the data which we have available.

We can also use existing data  in the follow-up of patients in order to compare information from people who have been treated with other drugs. Then you can look at the efficacy, “Is the product that has been approved, as efficacious as others that exist?” And further, “Are there subgroups of patients who respond to drug A, rather than drug B”? It’s a relatively new area but one which has great potential. There is also the possibility to develop areas such as pharmacogenomics and personalised medicine.

In summary, it’s about using the data that we have to inform the development of trials, the identification of patients who take part in trials, finding controls in the data which are suitable for orphan conditions, and then post-marketing follow-up.

NextLevel: What is the quality of RWD as opposed to clinical data?

KB: Clinical data is routinely collected as part of a normal assessment using agreed clinical rating scales. Quite often, this is in accordance with national HTA guidelines, such as NICE within the UK. RWD can also include patient feedback and tends to have some subjective outcomes such as an assessment of a patient’s quality of life. RWD has to take into account the context in which it has been entered. So, if it’s clinical data entered by a clinician, that has been considered as more robust rather than somebody saying, “I am feeling well,” or, “I am not feeling well.” However, both have their advantages and disadvantages and it is only when the two are combined that we can get a true picture of a patient’s overall health status.

In particular, we need to consider patient-reported outcomes measures (PROMs). These play a key role in assessing whether a drug is effective. For example, in the past I have spoken with a Parkinson’s clinician who said that usually he asks whether somebody can walk a certain distance or whether they have a tremor. However, what they may fail to ask, is, “How well have you been sleeping? Have you been eating?” In other words, how the disease is impacting on the patient’s quality of life. A lot of what is now included in registries and in patient data combines both the objective clinical outcome measures and the PROMs.

It is only by combining all these that we will get real insights into how a drug will impact the patients and their conditions. The MAAs coming to the CAT and to the other committees in the EMA now routinely include details of PROMs. It is only by combining the two of those that you get an in-depth understanding of whether a medication or treatment is working and the impact that it has on the patient.

However, the collection of all data – both clinical and PROMs – must be done in an appropriate fashion. Again, it goes back to data quality because of the “garbage in, garbage out” problem. We need to make sure all data to be used is collected in an appropriately robust and reproducible fashion so that it can be used appropriately.

NextLevel: What are you looking forward to most at our event in Zürich?

KB: I am looking forward to talking to other people who are using similar approaches for drug development. It’s really important to understand that we can share data and that we can combine approaches for the benefit of patients. Most of the datasets which have been made available to us at the EMA are from clinicians and patient groups and we want to build upon this in the future. So we need to encourage people to become involved.

There has been a hesitancy on behalf of the pharmaceutical industry to share data. What I would like to communicate to all the people there is that if we are to move forward in the development of new and more effective treatments for specific conditions, we need to make the best use of the data that is available. Ultimately, the data belongs to the patients and my experience is that they want this to be used optimally. We need to work together because that would be for everybody’s benefit. We need to have the total buy-in of all the stakeholders. Companies who have been working on clinical trials for years have immense amounts of data. We need to get that buy-in from everybody and ask ourselves, “What are we here for? We are here to improve the lives of patients, to develop new therapies, and to improve the treatments that are available to us.” We can only do this by working together.

For more information about this MedAffairs Leaders Forum Europe (Autumn) please click here!