Unusual unapproved drug action by FDA against Provident Pharmaceuticals

In an article by Wayne Heilman of the Colorado Springs Gazette, I learned of a US FDA action against contract drug manufacturer Provident Pharmaceuticals. The company has been cited for good manufacturing practices (GMP) violations as well as the manufacture of unapproved drugs. The GMP violations are of a magnitude that FDA requested that Provident hire a GMP training consultant to bring the facility up to snuff.

However, Heilman seized upon an interesting side light in the warning: the names of the unapproved drugs apparently made by the company are missing from the detailed warning letter.

By unapproved drugs, FDA means drugs whose safety and efficacy has not been formally investigated under modern criteria. Some of these agents are those which the average person might say, "Really? That was never approved? You're kidding, right?"

I suspect this is an innocent omission - I hypothesize that Provident wasn't doing anything nefarious - because FDA has been widely aggressive in acting against companies marketing such old drugs, a topic that deserves its own post. In the meantime, the reader may care to visit this Unapproved Drugs site at fda.gov.

A good example is the expectorant, guaifenesin, a natural product isolated for trees of the Guaiacum genus. This compound, a racemic mixture actually, was approved by FDA in 1952 to increase the volume and reduce the viscosity of respiratory secretions. However, it was never formally approved after the 1962 legislation that gave the US most of its current guidelines for preclinical and clinical drug testing.

When FDA began its current enforcement campaign against unapproved drug manufacturers, Reckitt Benckiser seized upon guaifenesin being an unapproved drug, brought it up to modern standards, and now has a top-selling product with Mucinex, accompanied by those animated mucus blob characters that either charm or repulse.

I hope that things get straightened out for Provident, a company with 44 employees two years ago that has now grown to 70. They have largely been a success story for the southern end of the Boulder-Denver-Colorado Springs biotechnology corridor, an area that was featured in 2007 as a technology hub by Site Selection magazine.

Provident is led by Dr Brian Crook, a Colorado State University BS and DVM graduate who cuts his teeth in pharma with Merck and Centocor. (Although he did unwisely introduce himself in this article as, "A Crook who sells drugs" - bad branding my social media peeps might say.)

Colo Spgs.jpg

I don't have any relationship with Dr Crook or any of the companies with which he is or was affiliated. I'm just a big booster of the Colorado Springs area and its educational institutions. The Springs are home to the Biological Sciences Curriculum Study (BSCS), a non-profit organization that develops curricular materials for agencies like NIH or NSF and makes many of them available to teachers free of charge. We featured BSCS here in 2006 and 2008.

The city is also home to Colorado College, a superb, private four-year arts and sciences college where I have had the honor of guest lecturing. Their unique "Block Plan", taking one intensive course at a time, provides such intensive, experiential, and refreshing collegiate experiences that I've known several CU-Boulder and Denver faculty members to send their kids there over Colorado's flagship university.

Across town, the University of Colorado at Colorado Springs also recently opened a $56 million, 156,000 sq ft science and engineering building on their campus. (UCCS is also home to psychology professor and CU President's Teaching Scholar, Fred Coolidge, PhD, guitarist in the band Pink Freud.)

So, I hope that this case with Provident comes to some resolution for the best of the company and their Colorado Springs employees. Moreover, I hope that my educator colleagues there might seize upon this episode for a case study of the pharmaceutical industry, FDA regulations, and the history of pharmacology.


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Some of the "unapproved" drugs the FDA has issued "warning letters" for have been marketed and sold in the US since before the FDA existed. Codeine, morphine sulfate, asprin and Tylenol. All of those manufacturers assumed those substances were "grandfathered". The FDA has alot on its plate with it now regulating food, drugs and the marketing of tobacco. Maybe they should be split in 3? Food regulation can go back to the Department of Agriculture, tobacco can go back to Alcohol, Tobacco and Firearms, and that will leave only commercially manufactured drugs for the FDA. Then, maybe they could handle approving new drug applications and not wasting time and money punishing small companies for manufacturing drugs with a history of safe and effective uses.

I have also had the honor of lecturing at CC, actually for a full Block. I suspect this has something to do with the fact that I am an alumnus as well. It is indeed a fantastic small college environment and many find the unusual academic plan to be helpful. I would submit that it is very good preparation for subsequent graduate education in the sciences...a sustained intellectual focus on a single topic for extended periods ring any bells?

Perhaps unusually for a school of less than 2,000 undergraduates it also features DivI Women's Soccer and Men's Hockey.

You should probably point out that C Springs is also home to the Air Force Academy, another bachelor's level institution which, as you can imagine, is very strong in science and engineering...

@Kelly - I've been very interested to know why all this effort is being expended on old drugs that were thought, by me included, to have been grandfathered in or addressed in the Drug Efficacy Reviews commissioned by FDA from the National Academy of Sciences in the mid-1960s. Perhaps that FDA could only go after dietary supplement manufacturers selling unapproved drugs if they also held current drug manufacturers to the same rules.

@mat - Indeed, CC has some incredible Division I sports for a school its size. I'd go see them play the University of Denver (DU) and be just amazed at the level of play from a couple of small schools. Much better (and far less expensive) than seeing the Colorado Avalanche.

And shame on me for neglecting the US Air Force Academy - if you don't see the stadium against the foothills, surely I could be reminded of the two Academy Blvd exits on I-25.

Not only does the Academy have fantastic science and technology, but it draws a large number of military retirees (together with nearby Fort Carson, Peterson Air Force Base, and the Cheyenne Mountain NORAD facility). This community creates a rich resource of amazingly accomplished professionals looking to continue in working retirement and is advertised by the city in recruiting new tech-based businesses.

Like many places in the West, there are conservative extremes (such as Douglas Bruce and James Dobson's Focus on the Family) but these are mostly institutional. You'll equally find a bunch of environmentalists, hipsters, and other socialists there - for those hitting on this post looking for information, take a gander at the Colorado Springs Independent, the area's alt-weekly fishwrapper.

The reasoning behind the FDA targeting "grandfathered" drugs and compounded medication is the mighty dollar. The FDA has become one of the largest divisions of the US government. They have expanded to tabacco, food, dietary supplements, drugs and have attempted to regulate compounding. To accomplish each of these tasks they will need to hire many more agents and mid level managers. Where to find the funds? Require all drugs to have New Drug Apllications and Fees. The FDA should be broken up in to smaller government agencies as quickly as possible.

It may be surprising to realize that companies introduce new unapproved drugs routinely with some of these older ingredients -- seemingly without regard to whether the formulation, patient populations, and labeled dosing are safe or effective. Health professionals prescribe and dispense them without realizing there are risks associated with many of them. Consider the example of prescription infant cough/cold products--specifically labeled for infants as young as one month of age (with AGE-based dosing). Many contain brompheniramine or another antihistamine with a decongestant and/or cough suppressant. There is no evidence to support safety or efficacy in children this young - in fact evidence supports NOT using them. There are no such products approved by FDA for infants this young - yet there are multiple such prescription products on the market...with labeled dosing recommendations that have never been reviewed by FDA or scrutinized by anyone beyond the manufacturer); these recommendations get integrated into our drug information references...and the misperception-cycle continues. The unapproved drugs situation is a bigger problem with greater patient risks than many in healthcare realize - although that is beginning to change. Look to recent issues of Pediatrics for articles in the past year and a half related to adverse events including deaths in young infants. Awareness is increasing - and many of us are shocked to realize the magnitude of the problem. Incidentally, FDA does not charge fees for ANDAs; they also have assistance programs for working with small companies to help them bring their products into compliance when an NDA is required.