Clinical continuity: the commercial role of phase IV studies

Paul Tunnah interviews Riccardo Perfetti

Sanofi

Effective clinical trial design has always been a critical component of ensuring new drugs receive the right commercial positioning and can reach the patients that really need them. As trial design plays an ever more important role in not only achieving regulatory approval, but also ensuring market access it has become vital to ensure that multiple perspectives from within pharma are accounted for.

However, once approval has been secured there is a need for ongoing clinical activity in the guise of phase IV studies. Far from being “nice to have” components of the development programme, these trials often play a vital role in expanding or securing the market position for a new drug, particularly where the landscape into which it launches has moved on since the pivotal phase III study.

Ahead of his talk at the 4th Annual Best Practice in Phase IV Clinical &amp, Observational Research conference in the UK in October, pharmaphorum speaks with Riccardo Perfetti, from Sanofi, to hear his expert perspective on the role of phase IV studies. Here, he explains how their planning starts way before approval, the key role they play, what factors need to be considered in their design and how successful phase IV studies can significantly alter the market dynamic for a medicine.

To listen to the full interview, please click on the play button below, with a shortened transcript of some edited highlights shown in print below.

Interview summary

PT: Riccardo, thanks for joining me today. First of all, why do we need phase IV studies once a drug has been approved?

RP: Phase IV studies are clinical activities that take place after a drug has been approved, typically to respond to potential comparative effectiveness versus a new entry on the marketplace. So they’re used to compare and contrast the efficacy and safety within the approved indication versus comparator molecules that were not available during development. They can also serve an additional purpose though in supporting expanding the drug label, for example where a drug is already approved for diabetes but not necessarily licensed for use in a paediatric population. In addition, phase IV data could be used when looking for a completely new indication, which may have been unforeseen at the original time of development. So there are numerous areas for which a phase IV study could be conducted to support a drug that has been already approved.

PT: How do the phase IV studies differ to the pre-registration phase III studies?

RP: Phase III studies are really designed to meet the expectations of regulatory authorities, so in terms of clinical study design and size they are very similar for different drugs within the same class. Any new drug that gets in the marketplace needs to differentiate itself, so phase III studies are typically aiming at proving differential safety and efficacy. Phase IV studies need to be a bit more creative, especially if they are not for a first-in-class indication. For instance, the endpoint of a typical phase III diabetes study is the level of HbA1c, the endpoint for an LDL cholesterol lowering drug is the level of LDL cholesterol and so on. The phase IV study could be more creative, so could look at LDL cholesterol levels without the side effects that you may observe in association with a statin, or assess glucose lowering with less incidence of hypoglycaemia. So phase IV studies, in terms of design and endpoints, are a little bit more sophisticated than simply meeting the scientific requirements of registration goals.

“For example, a drug that needs to be taken three times a day is typically associated with less favourable compliance…”

PT: And phase IV studies can be conducted either as randomised control studies or observational studies, so how do you determine the best route?

RP: The gold standard of scientific evidence remains the randomised control study, because here you will allocate patients to different treatment options independently from the characteristics of the patient. So the outcome of the study is driven supposedly by the drug, not by any biased selection. But in reality in a randomised control study you can create an artificial situation by which patients are actually very aggressively monitored to favour compliance, while in real life compliance is governed by things that go beyond the pure efficacy. For example, a drug that needs to be taken three times a day is typically associated with less favourable compliance than a drug taken once a week, but in a randomised study this difference would disappear if they have the same potency and efficacy. However, in real life, as with an observational study, you may see something that is less artificial – this introduces a bit more of the real drivers to success and failure that we see in practice.

PT: So phase IV studies can actually provide additional information that wouldn’t necessarily be captured during the pre-registration trials?

RP: Today, almost every company tries to make its phase III studies robust enough to minimise the need for phase IV, but in reality this is quite impossible because you can only do phase III studies with the comparators that are available at the time you are designing. So if another company is also developing a new compound in the same disease area while you are developing your phase III trial there will always be a need for a future phase IV study.

PT: At what point in the development cycle does planning for phase IV studies normally begin?

RP: At least a couple of years before filing for registration one starts thinking about what will need to be integrated, because other new molecules may be under development at the same time as outlined above. So you make a compromise, with your first objective being filing for registration and your secondary objective to make your value proposition stronger by complimenting what you have already generated with new phase IV study.

PT: What are the key things that need to be factored in to phase IV studies and what are the common pitfalls to avoid?

RP: Obviously phase IV studies are riskier because they need to be a little bit more creative, with more assumption involved about what data needs to be generated at the time of study design. So one risk is that you may not know enough about your drug at the time when you design your phase IV, particularly if you then encounter a subpopulation of individuals that may have a different response, which could skew the phase IV study design in an unfavourable way.

“..no new LDL lowering agent will ever be successful if it doesn’t produce cardiovascular benefit data.”

PT: Are there examples of phase IV studies that have really helped with market access for a drug?

RP: Certainly the statins are a good example here. They not only lower LDL but can also reduce cardiovascular mortality, as shown by phase IV data, so no new LDL lowering agent will ever be successful if it doesn’t produce cardiovascular benefit data. So the statins have created precedence where in addition to changing the LDL biomarker they also improve mortality and this has significantly changed the opportunity for this class.

PT: Where should phase IV planning and operation sit within big pharma in order to be effective?

RP: Typically in medical affairs, where they attempt to respond to the complexity of options experienced in real life drug use. Phase IV studies need to be harmonised with the commercial value proposition so they are not purely addressing scientific questions, which makes medical affairs the most appropriate home.

About the interviewee:

Dr. Riccardo Perfetti is currently the VP Medical Affairs of the Global Diabetes Division team, in the Paris Global Headquarter. He received his medical training in University “La Sapienza,” Rome, Italy in 1985 and completed his Endocrinology training in 1989 with his thesis looking at “Identification of an insulin-like growth factor-binding protein synthesized by mouse glomerular mesangial cells in culture”. He continued his training achieving a PhD in Molecular Endocrinology in 1995 from La Sapienza and The Johns Hopkins University.

Prior to joining sanofi-aventis in autumn 2007, Dr. Perfetti held a variety of positions in Amgen Inc over a 3 year period, including Director, Department of Medical Sciences, Global Development Leader responsible for designing and executing from phase 2a- to registration clinical studies for type 2 diabetes, obesity, metabolism, and endocrinology programmes, and Biomarker Development Team Member for first-in-class, Diabetes, Metabolism and Endocrine Group.

Riccardo will be speaking at the upcoming 4th Annual Best Practice in Phase IV Clinical &amp, Observational Research conference in the UK.

What defines best practice with phase IV studies?