Elke Bestel, Chief Medical Officer at PregLem , shares some of the best practices for conducting Phase IV trials, the benefits of doing so and how to overcome specific challenges of post-clinical testing.

CTA : What are the benefits of conducting Phase IV trials?

EB: The majority of post-approval studies we are conducting are mandatory in order to maintain approval, i.e. the so called Pass (Post-Authorisation Safety Study).

Apart from fulfilling the mandatory PASS, some additional benefits come from the marketing side. If you enter the market with a new drug, a phase IV trial will make the drug known and physicians more aware of it. If you do not create awareness, your new drug can be on the market, but the physicians will not think about prescribing it. They have to be aware that there is a new drug with a good safety profile that is possibly more effective than existing drugs available. For example, in phase IV trials, you might have key opinion leaders participating who will know and talk about your drug. They might say they have had a good experience and that their patients are happy with it. Afterwards, these KOLs can talk in congresses about your new drug as good publicity. By having participated in a well-designed trial, all participating physicians will put the drug into the inventory of medications and think about this new drug when prescribing for the respective condition. I think it is worth conducting phase IV studies because you will have more safety and more interesting data that will help you, and physicians, know your product better.

CTA: What are some of the best practices for conducting phase IV trials?

EB: It depends on the trial. You have to be rigorous with your protocol, think about how you will extract your data and what you will get out of the study. You cannot run a phase IV study like you run a phase III study. You cannot ask for the same measurements and details. Phase IV needs to adapt to real-world data and clinical practices, which are different in a lot of countries. You have to think about what you may get out of this data. In a phase III you pay attention to every little thing and limit your patient population. In phase IV you broaden your patient population, so you will have more interfering factors with your results.
We say that with a long treatment, as in phase IV, what matters is the patient's and physician's satisfaction, not the measure of a lab value or the size of an assessment. It is what the physician finally thinks and what the patient finally thinks of the product that is of most important. So, we simplified enormously the CRF compared with the original phase III and we integrated the satisfaction of the physician and patients as key endpoints. We also have phase IV non-interventional studies, where we cannot ask for the same measurements because otherwise we become interventional. For example, we work with fibroids. The fibroid size, whether it measures 2cm or 3cm, is not the patient's problem. The patient's problem is how much the fibroid will annoy her in her daily life; if she bleeds, has pain or pressure symptoms.

CTA: What have been the results of conducting phase IV trials for your company so far?

EB: For the time being, we have not had any unexpected results. This is probably due to the change in endpoints linked to the real-world data which avoided disappointment after the end of the study.

CTA; What has been the impact to PregLem on doing these trials? For example, are you getting more sales as a result of this?

EB: It is difficult to assess how sales would have been without performing the study, so this is not easy to answer. Most likely, "yes", I would say. As we had to start this PASS immediately after approval, we could not evaluate sales before the trial and after it. But the study was a big success in the participating countries. The interest of physicians was high, as they were curious to use the new drug. And now our KOLs are happy to report regularly on interim results of this study. Our marketing teams appreciate the easy access to physicians and overall all participants consider this study a success.

CTA: In your opinion, what is the reason why phase IV trials often fail?

EB: Maybe what is missing from a lot of companies is that they do not put the same attention to phase IV studies as to phase III. If you fail phase IV, it is annoying but your product is not at risk. Generally you have less money for phase IV and people pay much less attention to it.

CTA: Is there a way to make all pharma companies pay enough attention to phase IV?

EB: It depends on how much attention and money they are willing to give in this space. It is not always an obligation; it is more a question of reputation. If they do not put enough attention, they will not get the expected results.

CTA: How can we overcome the challenge of patient recruitment for phase IV trials, where there is a broader patient population?

EB: Your protocol should be attractive to the investigators, so that they are interested in participating. Otherwise, you will not recruit. Physicians are not only interested in money; Offering them the possibility to publish or talk in congresses, providing new knowledge about the drug, compiling an easy-to-follow protocol, and an easy-to-follow CRF are items which will help recruitment and follow-up within your study.

You may broaden your population in comparison to phase III and have less exclusion criteria, but this bears the risk of interfering factors, which need to be evaluated and may influence your results. But getting this new information will nevertheless increase the knowledge of your drug, which is good for your company.

CTA: Has this strategy worked well for you?

EB: Yes, it worked well for us. It is not easy to identify what has been the ultimate reason for successful recruitment. If you have an interesting drug and a good protocol, but the actual work on the study is difficult due to a badly designed eCRF or due to poor interaction with the CRO (just to mention a few potential issues), you will lose your physicians and patients.

Generally, I would say you should pay attention to every single step in order to make your study successful: it starts with a well-designed protocol and eCRF, but continues with a good study team (including the CRO!), motivated physicians, including KOLs, and an efficient communication between all parties. It is important to consider the work of physicians as key for a study to be successful.