Regulatory: FDA Exempts Phase 1 drugs from Part211

A couple of weeks (15-July) ago the FDA issued Docket FDA-2005-N-0170-0005. This lays out their decision to exempt Phase 1 investigational drugs from the requirements of Part211;

(c) An investigational drug for use in a phase 1 study, as described in
§ 312.21(a) of this chapter, is subject to the statutory requirements set forth in
21 U.S.C. 351(a)(2)(B). The production of such drug is exempt from compliance
with the regulations in part 211 of this chapter. However, this exemption does
not apply to an investigational drug for use in a phase 1 study once the
investigational drug has been made available for use by or for the sponsor
in a phase 2 or phase 3 study, as described in § 312.21(b) and (c) of this
chapter, or the drug has been lawfully marketed. If the investigational drug has
been made available in a phase 2 or phase 3 study or the drug has been
lawfully marketed, the drug for use in the phase 1 study must comply with
part 211.

Now here's what confuses me. In the preamble to this, the FDA state:

FDA believes this change...is appropriate because many of the issues
presented by the production of investigational drugs intended for use
in the relatively small phase 1 clinical trials are different from
issues presented by the production of drug products for
use in the larger phase 2 and phase 3 clinical trials or for commercial
marketing.

OK, so far so good, that makes sense...

Additionally, many of the specific requirements in the regulations in part
211 do not apply to the conditions under which many drugs for use in
phase 1 clinical trials are produced. For example, the concerns underlying the
regulations’ requirement for fully validated manufacturing processes,
rotation of the stock for drug product containers, the repackaging and
relabeling of drug products, and separate packaging and production areas
are generally not concerns for these very limited production investigational drug
products used in phase 1 clinical trials.

So this is a nice, clear rationale for exempting these types of drugs; risk-based and scientific.

BUT then they throw in a caveat...

However, once an investigational drug product has been manufactured by, or for,
a sponsor and is available for use in a phase 2 or phase 3 study, thus demonstrating
an intent to expose more subjects to the investigational drug and requiring that
the regulations’ CGMP requirements be met, the same investigational drug
product used in any subsequent phase 1 study by the same sponsor must be
manufactured in compliance with part 211.

So, you scale up production for Phase 2/3 and apply Part211 processes and controls, fine. But then if you decide to return to do a second Phase 1 trial, all those good reasons for not applying Part 211 cease to be valid!? How does that work? Surely, if I scrap a Phase 2 trial and want to repeat Phase 1 (for whatever reason) there exist the same, risk-based, scientific reasons for exempting the drug, i.e. small batches, stock rotation not feasible, repackaging and relabelling?
And then to top it all off, this only applies to when the same Sponsor does it. Meaning Sponsor A does Phase 1 under an IND, then does a Phase 2 under Part 211, then goes and does Phase 1 again, but this time has to still apply Part 211. Subsequently, along comes Sponsor B with the same drug, doing Phase 1 but only using an IND. OK, if the drug is commercially marketed and then goes through a Phase 1 trial for another indication, apply Part211 since the drug samples for trial will be just taken from the commercial stock, no problems.

So much for clarity. I have read most of the preamble and cannot see either a comment pointing out this scenario or any explanation of why the FDA have made the rule this way. So I must be missing something very obvious...let me know if you can see why a Phase 1 drug should be treated any differently before or after it has passed through another Phase.

The European Compliance Academy also reports on this here.