TCS Daily


Be the One

By James Pinkerton - July 17, 2006 12:00 AM

One Pill to Heal Them All. Those words -- apologies to J.R.R. Tolkien's "one ring to rule them all" -- kept going through my mind as I attended Wednesday's press conference spearheaded by acting Food and Drug Administration Commissioner Dr. Andrew von Eschenbach, at which the federal government announced its approval of Atripla, a new three-in-one AIDS medicine.

Gilead Sciences and Bristol-Myers Squibb have worked together to combine three medicines (Sustiva, Emtriva, and Viread) into one single pill. As noted, One Pill To Heal Them All. But, one might protest, isn't it overstating things to wax rhapsodic about a new medicine that merely combines existing medicines? Isn't Atripla, after all, just...another pill?

Well, the serious and senior government officials -- Medical Doctors all -- who are closest to the situation are vocal in proclaiming that Atripla is a big, big deal. Let's listen to them: First up was FDA chief von Eschenbach, who declared that the triune nature of Atripla represented "a new paradigm" of medicine, comparing the pill to the laptop computer -- all the parts and components squeezed into one cool and compact tool. And his deputy at the FDA, Dr. Murray Lumpkin, referred to the idea behind Atripla as "the holy grail" of medicine. These are health-and-safety regulators talking; they get paid to focus mostly on the downside of whatever it is that comes before them. So if von Eschenbach invokes Thomas "Paradigm Shift" Kuhn, of Structure of Scientific Revolutions fame, then maybe this is a big deal. And if Lumpkin can cite the Grail Legend, maybe Atripla is an even bigger deal, right up there with the greatest of medical breakthroughs.

The enormous value of Atripla becomes manifest when one considers the difficulty of keeping track of a complicated pill-taking regimen -- which is all the more difficult for the sick. The more "moving parts," as it were, in the course of treatment, the greater the risk of under-dosing or over-dosing. In addition, an increase in the number of discrete medicines in a specific programme also increases the danger of storage and delivery SNAFUs. As Lumpkin explained, "The number of pills to take is inversely proportional to good health outcomes." And of course, if one moves the problem to the Third World -- home to most AIDS victims -- where literacy levels are low and where the medical and transportation infrastructure is minimal-to-non-existent, then the lifesaving power of simplicity becomes even more palpable.

As von von Eschenbach put it, "Compliance with treatment is as important as the treatment itself." If one can't take the medicine properly, for whatever reason, then the good effect of the medicine is lost. Indeed, the problem of mistreatment is worse than that; scientists know that if adherence to a prescribed regimen falls below 95 percent, not only will the medicine fail to help the patient, but the danger of adaptive mutation -- as the bug "learns" how to survive the medicine -- increases dramatically. That's what has happened as a result of sloppy administration of tuberculosis medicines; new and improved TB germs are on the loose, killing more than in many years. It would be an even greater tragedy if the HIV/AIDS virus were to get the same "opportunity."

So the One Pill Paradigm is powerful, in and of itself. But the idea of the One Big Thing, which unifies many things, resonates throughout our entire culture, through the history of technological advancement. In fact, one way to measure progress is to measure the trend toward the simplification and unification of disparate strands of technology. The goal -- the grail, even -- is to get everything into one user-friendly package.

Paradoxically, perhaps the most obvious example of such a unifying merger of components comes from an area that's far away from lifesaving: the bullet cartridge. According to Wikipedia, the idea of the cartridge -- a charge of powder and a bullet in a paper tube -- first appeared in the 16th century. But the idea didn't take off till the mid-19th century, when the percussion cap was invented. It was the percussion cap that made the cartridge (that phrase was soon simplified down to "bullet") so lethally effective: thanks to cartridged bullets, the firearm could be loaded, discharged, and reloaded quickly, in any kind of weather, without the hassle of such trouble-prone parts as flints and powder pans.

Of course, the technical improvement of the bullet was just a part of the process of "cartridge-izing" other items, from food (in the form of cans and other packages -- think Spam) to film and audio tapes (cassettes) to electronics (integrated and solid-state circuitry). On a physically larger scale, author Brian Cudahy makes some ambitious claims for cargo containers, as seen in the title of his recent book: Box Boats: How Container Ships Changed the World.

The idea of Oneness has great power in other realms, too: Everyone, for example, wants a Universal Remote to control all their gadgets, even if sometimes the plan can go a bit haywire. And of course, everyone looks forward to the day when the telephone, the TV, and the computer are all made one, with one single simple line coming in to, and out of, the home.

There is one problem, of course. While it's important to think of the idea of holism, it's even more important actually to figure out how to achieve it. As we have seen, it took the better part of three centuries to turn the idea of the bullet-cartridge into the reality of the bullet-cartridge. And the same holds true for medicine; the One Pill Paradigm has been around for awhile, in the form of multivitamins, but when medicines get complicated, the manufacturing gets even more complicated.

So meet Dr. Taiyin Yang, the senior vice president for development and manufacturing at Gilead, who was present at von Eschenbach's press conference. She told me that it took more than 20 person-years -- 15 people working full time for a year-and-a-half -- to make the One Pill idea work. The key is "bi-layer compression" (which I can't explain any more than I can explain the innards of a laptop computer).

But I don't have to understand it, and neither do you. The point is that it works. And now that Pharma companies and the FDA have established a workable template for One Pill-izing complicated medicines, other combo products are likely to emerge.

Thanks to the miracle of science, and also the miracle of the free marketplace -- and the further miracle of a federal government that managed to approve Atripla in a mere three months -- a new lifesaving product is on the market, offering hope to millions.

I don't know if anyone will ever write a book about this "One-izing" process, but somebody should, because it's a huge story. It's a saga of hard work and vision, featuring more heroes than even Tolkien could dream of.

James Pinkerton is TCS Daily's media critic and a fellow with the New America Foundation.

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12 Comments

Amazing Article
Anything with elderly relatives or friends should realize all the potential error points in delivering prescribed medication to the patient. These range from misreading labels to losing medications to altering doses or arbitrarily stopping medications based on hunches, bad advice, a scary news story, or maybe a spouse who things (s)he's a doctor. Mismedication leads to all sorts of problems, many requiring expensive hospitalization. Cutting down on it is a sure way to reduce costs and improve quality of care.

While this AIDS drug is the beginning of this kind of drug bundling, the long term goal needs to be customized bundling of medication as close to the patient as possible. Perhaps in 10 or 20 years, when many of us start to become the best customers of the pharma companies (haha), we'll have periodic blood testing, automated diet evaluation, and customized doses mixed for us every week or every day to effectively manage our afflictions. Being old in 40 years will be a piece of cake!

What if Atripla was not an AIDS drug?
If Atripla was not an AIDS drug, how long would the approval process have taken? If it was a weight-loss drug combination, or a diabetes treatment, how many additional tests or evaluations would the FDA have called for?

The fact that Atripla is an AIDS treatment gets it on the politically correct fast track to approval, but many other drugs are either held up or not approved because they are not sufficiently politically popular.
As a government agency, the FDA inevitably has to ask itself whether a drug is sufficiently safe to risk facing Congressional hearings over. It is much safer to deny approval or tie drugs up in red tape than to approve them and risk angry Senators.

One paragraph from Dr. Henry I. Miller's 21 March, 2006 article called "New Drug Demagoguery":

American pharmaceuticals are the most intensively tested products in history. Moving a drug through laboratory studies and then animal and human testing requires on average 12-15 years and more than $800 million in direct and indirect costs. By the time a drug company applies to the FDA for marketing approval of a new product, on average it has performed more than 70 clinical studies on at least 4,000 patients.

Dr. Miller also notes in an excellent 01 Sep 2004 article, "The Truth About Marcia Angell," that the FDA has stood in the way of tailoring medicines to fit the needs of each individual, a major development previously discussed by BoscoH.

The FDA, and the nanny-state philosophy that patients and their doctors cannot decide what drugs and accompanying risks they are willing to take, is the main barrier to pharmaceutical advances in this country.

I cannot pretend to know enough about this area to answer the logical question, and so I ask you: What can we do to replace the FDA?

A clarification...
I included the paragraph from Dr. Miller's "New Drug Demagoguery" to illustrate the hurdles and development timeframe that most drugs face. Compared to Atripla, most drugs face an uphill charge over open ground against an entrenched enemy machinegun emplacement. Atripla's approval was more like a rough day at boot camp.

I would also highly recommend "The Truth About Marcia Angell," another of the good Doctor's articles that deals with quite a bit of the anti-pharmaceutical company hysteria that seems so prevalent.

Sorry for any confusion.

Waste of Space
Talk about a waste of space!! Lumkin and von Escenbach should have their heads --- or their bank accounts --- examined. One pill is nice to simplify dosage and complaince. What they forget to say is that, in HIV/AIDS patients, the virus develops resistances to the drugs that are used. As a result, regimens for these patients can change as often as every six months. So --- do they propose taking ALL of the HIV drugs and doing combinations and permutations of these drugs so that they can cope with all of the resistances that occur AND simplify compliance? I think not. One-shot miracle product? No flaming way!

Talk about missing the point.
"So --- do they propose taking ALL of the HIV drugs and doing combinations and permutations of these drugs so that they can cope with all of the resistances that occur AND simplify compliance?"

Yeah, that's the coming trend. Totally personalized, mutli-company, single pill delivery, adjusted weekly or daily to the vitals of the patient. Probably "assembled" by your local pharmacist. This is as much about a coming change in drug economics and regulation as it is about simplified dosage and improved compliance.

This invention is to the drug industry what the laser printer was to desktop publishing 20 years ago. Super amazing stuff...

Not Missing the Point
Considering that I've been a consultant to the pharmaceutical industry for the past 26 years --- and have been in the biomedical fields for 33 years --- this ain't such hot stuff. Combination formulations have been done for ages and if it weren't for the fact that this addresses AIDS, it would fall in line with the rest of them. BTW: There are some 22 or so anti-HIV drugs on the market at the moment. To cover ALL of the drugs in combinations of 3 would require 188,000,000,000,000,000,000 different pills. So much for the "laser printer."

Correction
I forgot to hit the enter button on my calculator a second time --- the actual number of pills for all 22 drugs in combination of three would be 8,900,000. That's still impossible.

Math is bad too
It's besides the point, but the number of ways to choose 3 items from a palette of 22 is (22 x 21 x 20) / (3 x 2) = 1540. Simple combinatorics (lower division math).

Maybe we could make a bet at tradesports.com... Something like: "In 15 years, local pharmacists will be able to synthesize pills locally that combine dosages from multiple pills from multiple manufacturers, customized to particular patients' periodic blood tests and doctor's prescriptions."

I would go that specific, bringing revolutionary changes in technology, IP economics, and regulation together to yield the product. That's "the point".

No personalized combos until the FDA lightens up...
Until the FDA has a MAJOR shift in rules, the idea of local pharmacists personalizing a one-a-day pill for everybody will remain just that, an idea. That idea cannot be realized until the FDA has either been eliminated or undergone a major reform.

Furthermore, how vast a percentage of their resources would drug companies have to allocate to these drug combinations to get even a tenth of the possible combinations fast-track approval? This combination was possible because they are likely to make a sufficient amount of money off of it even after the approval process. How many of these theoretical combinations will accomplish that goal?

That's Right --- YOUR math is bad and your knowledge of the industry
The formula is M = n!/p!(n-p)! or M = 22!/3!(19!). (where n is the number of items and p is the number of items per combination.) I was a dual major (chemistry and math). And if you don't want to believe me, refer to the CRC Standard Mathematical Tables --- you lower grade mathematician --- not to mention that 1,540 would still be an excessive number of formulations IF your math was right. The standard pharmacy doesn't hold that many products in stock.

As for "In 15 years, local pharmacists will be able to synthesize pills locally that combine dosages from multiple pills from multiple manufacturers, customized to particular patients' periodic blood tests and doctor's prescriptions." Bullshit! You show your total ignorance of the field. First, pharmacists are no longer trained to do anything close to what your talking about here. Second, they wouldn't want to do it because of the liability. Third, they can't tabletize --- that actually takes dry environments and specialized equipment. And, while they can make capsules, their ability to do so accurately and for every material is limited. Fourth, formulating means that the pharmacist would have to keep raw inventory on hand for everything they formulate. This does not fit with pharmacy economics, which turns on limited inventory and JIT delivery of products. You also assume that pharmaceutical manufacturers want to supply such raw materials --- that doesn't fit their economics either.

No Subject
kgkphd wrote: "The formula is M = n!/p!(n-p)! or M = 22!/3!(19!)."

... which is exactly equal to (22*21*20)/(2*3)... just as BoscoH said :) Think it twice. Most of the factor in (n-p)! cancels with those same factors in n!, a nice trick when p is small enough.

If your knowledge about the industry is as good as your math...

Freman

Perhaps---
my math is not as good as it was 33 years ago. But I've forgotten more than you'll ever know.

And I KNOW my industry and NO pharmacy will do the things Bosco says they will.

Bosco should go back to chocolate milk.

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