Orphan Insights, Part 2: The PIP

Orphan Insights is a short series of Q&A assembled from the many discussions I have with companies developing medicines and therapies for rare diseases and who are seeking regulatory advice. These questions are related to when, why and how to engage with the regulators, and take advantage of the various designations applicable to their orphan programs. Each “Part” in this series will pose questions and offer strategic and thought-provoking responses. By no means are these straight forward answers, I hope however that you find the considerations helpful. I encourage you to reach out should you want to discuss anything further.

The PIP, PDCO and EU Pediatric regulation was all put into place in 2007 as a means to ensure medicines are being developed for children in a safe, ethical and timely manner.

A PIP as defined by the agency is a development plan aimed at ensuring that the necessary data are obtained through studies in children, to support the authorization of a medicine for children ages 0-17.

The scientific committee responsible for reviewing and authorizing PIPs is the PDCO or Pediatric Committee.

Question #1 – Do I need a PIP?

Yes. If you are planning to develop your medicine in the European Union, then you need to submit a PIP for adoption by the PDCO. Furthermore, a PIP (and compliance) is required for marketing authorization.

Question #2 – When is the right time to submit a PIP?

This depends on a lot of variables.

In general, it can be submitted prior to initiating trials and up until initial proof-of concept trials, definitely before pivotal or confirmatory trials.

Per the EMA, timing suggests no later than the end of human PK (healthy subjects or patients) data is acquired, with the understanding safety data is likely to coincide with this timing and before pivotal or confirmatory trials begin.

Certainly, having human safety and PK data, potentially in the target population where you can also measure some initial efficacy, would lead to a more in depth and thorough application and discussion.

Many variables come into play when you are developing a therapy for (1) a rare disease, (2) a rare pediatric disease and (3) when you are also considering when to apply for orphan designation (which was the basis for discussion in Part 1).

There are many incentives and flexibilities which therapies for rare diseases are granted in order to speed development and patient access to while maintaining safe and ethical forward movement. For instance, often a sponsor begins acquiring data in children from the onset of human trials. The EMA suggests this step prior to initiating trials in children but that may not always be the case and time.

With regards to orphan therapies, timing is sometimes dependent on whether the Sponsor has received Orphan Drug Designation.

Question #3 – Should Scientific Advice come before or after the PIP?

Scientific Advice (SA), or Protocol Assistance (PA, for orphans) can fall before or after the PIP procedure, just not during.

When SHOULD it?

The measures and timelines of the PDCO opinion are binding, yet can be modified with justification based on new findings. The SA/PA outcome is not binding, and the applicant and/or CHMP may justify diverging from the advice received during your PDCO engagement.

As I see it there are two paths for orphan medicines:

-> Orphan drug designation > protocol assistance > PIP

-> Orphan drug designation > PIP > protocol assistance

Yet there are many things to consider here:

1. Stage of development (see #2),
2. Your clinical development strategy,
3. Patient population (adult, pediatric or both?),
4. Eligibility to receive a PIP deferral or waiver, and
5. Risk/benefit in terms of both patients and corporate strategy.

Confused yet? While regulations are not meant to confuse you, they do, because they are written in general terms and have to speak (indirectly) to each product type and indication.

If you are still needing advice or clarification on your specific program I urge you to reach out.

Question #4 – Can I request a PIP deferral or waiver?

In some cases, yes.

The age range covered by a PIP is dictated by the PDCO and your objective going into a PIP may be to cover the whole population.

Where applicable, the PDCO considers that the best approach is inclusion of all ages in observational trials in order to acquire solid data. However, there are many cases where Sponsors for various reasons do not want to or cannot consider the whole population in their trials. There are many examples of this in our line of work, and when considering such rare populations.

A deferral suggests acquiring observational data post-marketing. In such a case, an MAA would be obtained at different timeframes for different age ranges, which could take many years.

A waiver may be applied to part or all of the pediatric population and is decided on a case by case basis. The most common reasons to make a request for waiver are when the medicine is likely to be ineffective or unsafe, is intended for an adult population, does not represent significant benefit to that populations (over existing treatments). Like a deferral, a waiver also needs to be justified and adopted.

Of course, there are exceptions to every case which may be considered.

If a waiver is granted, the Sponsor will be required to label accordingly. If this is not a desirable outcome, then other options need to be considered.

Summary

A successful regulatory affairs program requires careful, calculated and creative solutions. There are some regulations you cannot get around. And there are some regulations that you don’t want to miss out on. Every case is unique and for this, I encourage you to consider some of these points and questions.