Why Drug Development for Phase 2 Clinical Trials Is Like Opening Night On Broadway

The good news is your drug candidate has proven its safety and efficacy in Phase 1 clinical trials. That in itself is a big accomplishment. According to the FDA, only 33 percent of drugs make it from Phase 1 to Phase 2 trials. Like preparing for a Broadway production, it’s been rehearsal time until now.

Phase 2 is the point at which to consider making a substantial investment in your asset.

And now that your CMO is going to manufacture your New Chemical Entity (NCE) for Phase 2, new cGMP regulatory requirements come into play.

This article examines the top five reasons drug development costs for Phase 2 clinical trials can be substantially higher than for Phase 1.

Reason 1: Volumes increase substantially

Phase 1 clinical trials typically involve a small number of subjects – perhaps 10. When moving to

Phase 2, there is an order of magnitude increase in scale. Much more drug needs to be manufactured, as many more people – hundreds if not thousands — need to be tested.

As we previously described in Early/Late phase drug development blog, every drug development project involves creating new chemistry, doing things that have never been done before.

At the beginning of manufacturing for Phase 2, the processes still are not well understood yet. Not uncommonly, a process that works perfectly on the small scale required for Phase 1 trials may not work so well at the next stage.

In our decades of experience, approximately one in five projects encounters an unanticipated issue when moving into Phase 2.

Reason 2: Processing

Although Process Research makes every effort to identify and fix any process problems early on, manufacturing on larger scale is still fraught with potential problems. For example, sometimes when filtering a product it may not crystallize as it did at smaller scale.  Therefore, additional investment in process R&D may be needed and depending on the issue it could take extensive effort to solve it.

A new or tweaked process—and revised documentation — is required for any change made. And change in a process could potentially trigger a product safety concern by the FDA that must be addressed.

Reason 3: Impurities

Purification and extraction of high value chemicals from complex mixtures requires skill and experience. Over the past 20 years, PCI Synthesis’ chemists have developed proprietary extraction and purification techniques that generally work well.

However, sometimes purifications do not produce good results and the potential fix could drive costs up. Chemical processes create impurities that must be controlled to address the safety concerns of regulatory agencies.

Consequently, to move forward with Phase 2 trials, the NCE is subject to strict quality guidelines for acceptable levels of impurities. These guidelines are provided by the International Council for Harmonization (ICH).

Reason 4: Scale-up: moving from the Lab to the cGMP suite

For Phase 1 trials that involve just a few people, only small quantities of the NCE are required. These compounds are often prepared in the cGMP kilo lab, at a cost of $22,500 a week. For the much greater volume of drug required for Phase 2 trials, the process and analytics move to the cGMP plant, which costs $75,000 per week, more than 3 times as much.

Reason 5: Raw material costs

When the raw materials required are unique, custom-made, and required in larger quantity for Phase 2 manufacturing, they could cause problems in terms of quality, delivery, and performance.

Why Initiating Drug Development for Phase 2 Clinical Trials is Like a Broadway Opening Night

Before opening night on Broadway, every one of the actors and musicians spends a great deal of time practicing, learning their lines first for Act I then for Act II and so on. Similarly, in drug development, a great deal of time is spent on Process Research, moving from one step to the next.

Like rehearsals, we have scale-up, where we test the processes several times, increasing the quantity each time, before going into the manufacturing suite.

Opening night on Broadway is the first time actors, sets, lighting, music, stage direction, costumes and all the other show elements come together. Moving into cGMP manufacturing is similar –the chemicals, analytics and processes must come together for the first time – in much large volumes than ever before.

Like opening night on Broadway, the start of cGMP manufacturing does not always go smoothly. There are kinks to be worked out – but that’s not at all unusual.

The FDA Expects Problems

cGMP drug substance manufacturing is the most technically complex drug development task.

Because we are dealing with new chemistry that’s never been done before and because volumes increase for manufacturing, unanticipated problems can arise even with the best preparation, as we’ve outlined in this blog on commercial API production.  Yields can be less than anticipated. Impurities might materialize and processes are always being tweaked for greater efficiency.

This situation is common for the development of new drugs, although some sail smoothly through.  For many, the FDA anticipates numerous process problems and in its Guidance for Industry, they outline their concerns with:

• The pathway used to manufacture the drug substance:
• Material change in one of the bond forming steps.
• Change in a solvent used for the last reaction and/or crystallization step.
• Change resulting in a different impurity profile.
• The manufacturing process that can affect the quality of a drug substance.
• The manufacturing process that can directly or indirectly affect viral or impurity clearance for a drug substance.
• The manufacturing method from one manufacturing method (chemical synthesis, fermentation, or derivation from a natural source) to another.
• Source material or country of origin for a drug substance derived from a natural source.
• The method of sterilization of the drug substance or drug product.
• The drug product manufacturing process that can affect product quality.

There is one difference between Broadway and Phase 2 manufacturing: show stoppers receive extended applause on Broadway. That is not the case for pharmaceutical development.