About this Author
DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

Chemistry and Drug Data: Drugbank
Chempedia Lab
Synthetic Pages
Organic Chemistry Portal
Not Voodoo

Chemistry and Pharma Blogs:
Org Prep Daily
The Haystack
A New Merck, Reviewed
Liberal Arts Chemistry
Electron Pusher
All Things Metathesis
C&E News Blogs
Chemiotics II
Chemical Space
Noel O'Blog
In Vivo Blog
Terra Sigilatta
BBSRC/Douglas Kell
Realizations in Biostatistics
ChemSpider Blog
Organic Chem - Education & Industry
Pharma Strategy Blog
No Name No Slogan
Practical Fragments
The Curious Wavefunction
Natural Product Man
Fragment Literature
Chemistry World Blog
Synthetic Nature
Chemistry Blog
Synthesizing Ideas
Eye on FDA
Chemical Forums
Symyx Blog
Sceptical Chymist
Lamentations on Chemistry
Computational Organic Chemistry
Mining Drugs
Henry Rzepa

Science Blogs and News:
Bad Science
The Loom
Uncertain Principles
Fierce Biotech
Blogs for Industry
Omics! Omics!
Young Female Scientist
Notional Slurry
Nobel Intent
SciTech Daily
Science Blog
Gene Expression (I)
Gene Expression (II)
Adventures in Ethics and Science
Transterrestrial Musings
Slashdot Science
Cosmic Variance
Biology News Net

Medical Blogs
DB's Medical Rants
Science-Based Medicine
Respectful Insolence
Diabetes Mine

Economics and Business
Marginal Revolution
The Volokh Conspiracy
Knowledge Problem

Politics / Current Events
Virginia Postrel
Belmont Club
Mickey Kaus

Belles Lettres
Uncouth Reflections
Arts and Letters Daily
In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

« How Not to Do It: Ether Peroxides | Main | Various Updates »

January 15, 2006

The FDA Loosens Its Tie

Email This Entry

Posted by Derek

The FDA has released some new guidelines intended to make it easier to get drugs into the earliest stages of human trials. Considering how often we fail at those stages of development, anything that increases our number of shots on goal is good news.

The first part of the new approach is a set of official standards for what are known as "Exploratory INDs". (An IND (Investigational New Drug) application is the mound of paperwork that you have bring to the FDA in order to dose human subjects). What they're doing here is making it easier to test limited numbers of people at smaller doses, just to see if you can narrow down your drug candidates with some realistic data. This "microdosing" approach has been tried in Europe for the last few years, and it's definitely time the the agency laid out the rules for its application over here.

I think that for the most part the key data obtained in these trials will be pharmacokinetics - you could take three or four roughly equivalent drug candidates in and see which one had the best blood levels and distribution before committing yourself. (Fancy mass spectrometry techniques can allow you to see very small amounts of compound or metabolites in samples these days). This approach will also work out well if you have some sort of clinical marker that you trust. Sub-effective doses of the drug candidates could still point you to which ones are having the effect you want, if the signal-to-noise ratio of your surrogate marker is good enough. Imaging studies would be another good use for these trials.

If I'm reading their guidelines right, the FDA can let you go into human microdosing with only rat data. That sounds either exciting or alarming, depending on your point of view, but given the low doses involved, I think it's a good thing. For dosing up to pharmacologically active levels, though, they want the traditional rat/dog safety package, which is certainly reasonable.

The second part of the new standards are for manufacturing drug substances for these early trials. What they're doing, it seems, is loosening up the "Current Good Manufacturing Practice" rules a bit for small exploratory studies. This is mostly going to help out the smaller companies and (especially) academia. CGMP is no fun to follow if you're not set up for it, and it is rather odd to make the five-gram-batch folks jump through almost the same hoops as the five-thousand-kilo people. For the larger companies with lots of CGMP capacity, though, I don't see this change making much of a difference.

It'll be interesting to see what sort of coverage this gets in the press - assuming it gets much at all, that is. There's room for a sufficiently motivated complainer to go on about the FDA loosening up on its regulation of unknown toxic drug substances, poisoning America, slippery slope, etc. If any readers spot someone taking this tack, forward the reference to me, and I'll reward you with a laudatory mention here. It'll look great on your CV. Trust me.

Comments (10) + TrackBacks (0) | Category: Clinical Trials


1. Still Scared of Dinosaurs on January 16, 2006 4:39 AM writes...

I'm very interested in how this plays out. I've been amazed how much clinical development is held back by drug supply, but this is usually in the Phase 2 -> Phase3 step. I remember one VP of Regulatory stating "We WILL NOT commence a Phase 3 trial without having enough drug to dose all patients for the entire trial IN HOUSE." I infer from later observations that "in house" meant that production runs were scheduled some time soon, and this was for a biologic. Good thing the CHO cells were cooperative.
It seems to me that the rule change here will be a lot more helpful to drugs produced synthetically, which could give the industry a slight tilt in favor of pharma over biotech.

Permalink to Comment

2. Don B. on January 16, 2006 9:01 AM writes...


What level of non cGMP production do you see as appropriate? Some level of HPLC purity perhaps?

Don B.

Permalink to Comment

3. Dr Toot on January 16, 2006 3:35 PM writes...

With the $$$ spent on doggie health care in this country nowadays, I just kind of assume the Pink Sheet is an intermediate step to poor Alabamans being injected before the compund is taken into Fido.

Permalink to Comment

4. Alex on January 16, 2006 3:40 PM writes...

Could anyone give us an idea of what the requirements for CGMP work out to in practice? As in what is necessary to achieve those levels of purity?
Does production have to be in one big batch or are smaller batches OK?

Permalink to Comment

5. Derek Lowe on January 16, 2006 4:31 PM writes...

As to the CGMP purity issues, the draft FDA document is pretty vague:

"Analytical tests used in production (e.g., testing of components, in-process material, packaging, drug product) should be scientifically sound (e.g., specific, sensitive, and accurate) and reproducible for the specified purpose. We recommend that tests be performed under controlled conditions and follow written procedures describing the testing methodology.

Laboratory testing of the investigational product to evaluate identity, strength, potency, purity, and quality attributes should be performed, as appropriate. Specified attributes should be monitored, and acceptance criteria applied appropriately. . ."

And they address the problem of multiple batches, but also in rather general terms:

"We are aware that, in some cases, investigational biological and biotechnology products covered by this guidance may be produced as frequently as one batch per subject in phase 1 studies (e.g., therapeutic vaccines, cell therapies, gene therapies). Production of multiple batches will allow additional production and testing information to accumulate in an accelerated manner as compared to more conventional products. It is also important to have and adhere to appropriate control procedures that enable the consistent manufacture of comparable drug substance and drug products.

When producing multiple batches of the same investigational product, we recommend that producers periodically conduct and document internal performance reviews. . ."

Permalink to Comment

6. Michael Wren on January 17, 2006 12:40 PM writes...

This is really no more than an outright concession to PETA to limit preclinical animal testing, and use human test subjects -- utterly deplorable.

Permalink to Comment

7. Derek Lowe on January 17, 2006 1:24 PM writes...

Got to disagree with you there, assuming that that comment was meant to be taken seriously. This might even lead to a slight net increase in animal testing, as more compounds have a realistic shot at the clinic. And there are a lot of questions that can be answered only in humans. I'm gald to be able to get into people faster, myself, and you'd have a hard time finding a bigger defender of animal testing than I am.

Permalink to Comment

8. Don B. on January 18, 2006 11:30 AM writes...


Will you give a link for the FDA's Draft Regulations on this matter?

Don B.

Permalink to Comment

9. Derek Lowe on January 18, 2006 2:18 PM writes...

Don, the links (as far as I can tell the best ones) are in the post. The microdosing one is in paragraph 4, and the CGMP one is in paragraph 5. I think that's all they have so far.

Permalink to Comment

10. Don B. on January 19, 2006 9:50 AM writes...


Thanks! I went to an FDA link. It seems to be so general that once again you are in a crap shoot with the reviewer deciding if you have followed cGMP's.

Don B.

Permalink to Comment


Email this entry to:

Your email address:

Message (optional):

The Last Post
The GSK Layoffs Continue, By Proxy
The Move is Nigh
Another Alzheimer's IPO
Cutbacks at C&E News
Sanofi Pays to Get Back Into Oncology
An Irresponsible Statement About Curing Cancer
Oliver Sacks on Turning Back to Chemistry