Headline: Hospitals, patients run short of key drugs

Source: USA TODAY, 11 July 2001 URL: http://www.usatoday.com/hphoto.htm

Patricia DeRatto knows which local hospitals have stocks of the medicine that keeps her son from bleeding to death. Because the medicine has been in short supply for months, she's called them all to check, just in case.

The shortage means DeRatto sometimes doesn't have enough at home to last more than 24 hours if her son Daniel is seriously bleeding. "We've had minor shortages in the past, but it's never been this bad," says DeRatto of Chesterfield, Va.

The drug her son, 10, needs to treat his hemophilia isn't the only medicine missing from pharmacy shelves.

In the past few months, doctors and patients have faced shortages of more than a dozen medications, including snakebite treatment, surgical anesthetics, tetanus vaccine, steroids for premature infants, and antibiotics. And in late June, the Centers for Disease Control said that for the second-consecutive year, the flu vaccine may be delayed and supplies inadequate as the winter influenza season approaches.

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TABLE: Drugs that are now or were recently in short supply:

Drug Purpose Maker Reason

Tetanus vaccine Prevents tetanus Various One manufacturer discontinued product.

Isuprel Heart-attack treatment Abbott Labs Manufacturing difficulties.

Spectinomycin Gonorrhea treatment Pharmacia Discontinued by maker.

Norepinephrine Heart-attack treatment Abbott Manufacturing difficulties.

Kogenate Anti-clotting drug Bayer Manufacturing difficulties.

Antivenin Snake bite treatment Wyeth High demand; one maker to stop production by year's end.

Celestone Soluspan Anti-inflammatory Schering Manufacturing difficulties.

Narcan Counteracts narcotics Sabex Manufacturing difficulties.

Source: FDA and American Society of Health-System Pharmacists

---------------------------------------------------------------- Drug industry representatives say there's no cause for alarm, that only a handful of products are unavailable and that no long-term trend is developing.

But rather than getting better, many experts say, drug shortages are likely to get worse, the fallout of a health care system that's squeezed to its limit.

Critics say the government and drugmakers are doing little to address shortages or to warn the health care community and patients when shortages are about to occur.

"The financial incentive everywhere is to reduce costs. Until this whole health system blows up, nothing really is going to get done," says Dr. Bruce Cullen, chief of anesthesiology at Harborview Medical Center in Seattle. "What does it take — a few deaths — before it gets the attention of someone?"

Patients are being affected:

· Three Californians died in June after receiving injections of an anti-inflammatory drug made at a local pharmacy, which was asked by a surgical center to prepare the drug because the manufacturers' version is in short supply, according to the Contra Costa County Health Department. The doses were contaminated while being prepared.

· Doctors at the Naval Health Research Center in San Diego said two Navy recruits died last year of illnesses caused by adenoviruses, infections once prevented by a vaccine that is no longer made.

· People with hemophilia are being warned to delay elective surgery until production problems at a Bayer plant in California can be fixed. Parents are in a bind as summer heats up: Do they let children play sports, go camping, roughhouse?

"It's emotionally devastating," says DeRatto, who says she doesn't want to keep her son from a regular childhood. But with the shortage of clotting factor, she had to think twice before deciding to let him try out for an All Stars Pony League baseball team. "I don't want him to grow up feeling like he can't do anything."

· Some emphysema patients this spring went more than a month without prolastin, a drug that slows the disease's progression. "I could feel the difference," says Glenna Powell, 50, of Houston. "My activities ceased. I couldn't go anywhere or do anything."

· Hikers in areas with poisonous snakes were warned to be careful in May and June because demand for snakebite treatment outstripped supply. The supply is returning to normal, but manufacturer Wyeth will stop production by year's end. A British firm is preparing to produce the treatment.

· Public health officials want patients to delay routine tetanus vaccinations until next year, saving supplies for emergencies.

· At some hospitals earlier this year, morphine was substituted for what many doctors believe is a safer painkiller. "We came dangerously close to situations where there could have been an error, or we would have had to ration care," says Denise Jones of the American Society of Anesthesiologists.

But the pharmaceutical industry says the media is blowing shortages out of proportion. "We haven't seen definitive data that shows there is a problem," says Jeff Truwhitt of industry trade group Pharmaceutical Research and Manufacturers of America (PhRMA). "For the patients involved, it certainly is a big problem, but from a big-picture perspective, they've cited a handful of examples of shortages or stopped production out of 25,000 pharmaceutical products on the market."

Causes of shortages

The reasons for the shortages vary: hospitals carrying smaller inventories to save money; complicated pharmaceutical production processes; trouble getting raw materials; increased FDA enforcement of quality standards; and consolidation of the drug industry, leaving fewer manufacturers.

"It's a shrinking world. There are fewer manufacturers making the bulk materials and fewer making products," says Joseph Deffenbaugh, who monitors drug shortages for the American Society of Health-System Pharmacists.

Aside from problems with raw material shortages and industry consolidation, which are often out of the hands of regulators, some pharmacists and doctors say the government needs to provide better scrutiny when firms halt production of key drugs or vaccines. At the root of the issue is a clash between sound business principles — drugmakers deciding to stop making unprofitable products — and public health needs.

"The job of government is to help companies create a fair balance between these two," says Dr. Mohammad Akhter, executive director of the American Public Health Association, an advocacy and professional group. "Drug companies need to make a profit to continue to produce new drugs, but public health needs to be protected."

American Home Products, the parent company of Wyeth-Ayerst, in recent months decided to stop making the tetanus vaccine and Wydase, a drug used on newborns and surgery patients, because it would cost more to upgrade production facilities than the firm felt the products were worth. The company also decided to stop producing one dosage size of a surgical painkiller, fentanyl.

Other companies have made similar decisions. Pharmacia, for example, said in June that, because of low sales, it would halt production of spectinomycin, an antibiotic used to treat gonorrhea in pregnant women and patients allergic to other types of antibiotics.

"We conducted an evaluation of our product portfolio, taking into consideration a number of things," says spokesman Douglas Petkus of Wyeth-Ayerst Labs. "We do this periodically. Every pharmaceutical company does." Petkus says his firm gave adequate warning of the changes, although many doctors, public health officials and the FDA say they are often given little advance notice of such decisions.

Some drug firms have reversed decisions to halt production of products. Bayer, for example, last year decided to stop making Biltricide, a drug to treat parasitic diseases that are most commonly seen in Third World countries but do affect some U.S. tourists and immigrants. After tropical-disease doctors raised concerns, the company began producing it again.

In another example, production of a drug known as DEC, which treats a parasite that can cause elephantiasis, was halted. Wanting a supply, the CDC contracted with the college of pharmacy at the University of Iowa to produce the drug, an example of what may be one solution to the current drug shortage.

"I don't think we want the government to go into the pharmaceutical industry, but in a situation where they see a lack of essential drugs, the government should go out and find a supply," says Dr. Clinton White, an associate professor at Baylor College of Medicine.

Needed: Early warnings

Akhter says his group has asked the FDA to develop a better national monitoring system that would warn doctors, hospitals and patients when a shortage is expected.

"We have no drug-monitoring strategy in place," Akhter says.

The Food, Drug and Cosmetic Act requires that 6 months' notice be given by sole producers of "medically necessary" drugs before they halt production, but the rule is hard to enforce. Often, the FDA doesn't start its review of whether a drug is medically necessary until after it is already in short supply. And notice can't be given when a firm suddenly has production problems or can't get materials.

And there's little the FDA can do to punish companies that fail to report, because the agency can't assess civil fines, nor can it force companies to continue production.

"We have to give approval for companies to make the drugs, but companies can leave the marketplace anytime they wish," says Mark Goldberger, who coordinates the FDA's drug-shortage response.

Akhter and other health officials say drugmakers should be required to give a year's notice before halting production of a key drug. That would help public health officials plan for shortages — and might mean another manufacturer would step in to fill the supply.

"Progress in the FDA is very, very slow," Akhter says. "There's a lack of leadership at the top. The new administration has been in for 5 months, and there's still no FDA director and no (nominee) on the horizon."

FDA considers new tack

Goldberger could not comment on the search for an FDA director but said the agency is considering whether it needs to find new ways to deal with companies that are simply deciding to halt production: "This would be a major policy discussion and, ultimately, would have to go to Congress." In the meantime, "We would like to talk more with industry and see if there are things we can do without legislation to improve communication."

Hospitals say they need more notice than they get now, because many have shifted to a cost-control method known as just-in-time inventory, meaning they keep smaller inventories to avoid spending money before they need the drugs.

"If the FDA notifies us, and sometimes they're the last to hear, we immediately put out a broadcast to our community," says Harold Godwin, director of pharmacy at the University of Kansas Medical Center in Kansas City, Kan. "But our notice may be a day, if that. And we may only have a day or two supply on the shelf."

Requiring more warnings from drugmakers would require new laws from Congress. No hearings have been scheduled on the drug shortage, but it has raised concern among some members.

"Public health authorities, physicians and American families must receive early notice if a company stops production on any vaccine," says Rep. Henry Waxman, D-Calif. "Vaccine manufacturers receive a number of special incentives and legal protections from the government. Such advance notice is the least we can expect in return."

But more regulation of drugmakers is not what is needed, the pharmaceutical industry says.

Some drug industry leaders say hospitals need to look at their own inventory practices. "Just-in-time inventory is based on average use. If you have above-average use, then you have an issue," says Alan Goldhammer, vice president of regulatory affairs for the industry trade group PhRMA.

Price caps also hinder production, the group says. "Most of the vaccine market is effectively price-controlled, so there is not a true market for vaccines," says Sara Radcliffe, research director for PhRMA. She said those controls help explain why the number of vaccine makers has dropped from a dozen 15 years ago to four today.

Radcliffe's concern about vaccine price controls stems from federal legislation enacted in 1994. The law capped at 1993 levels the prices of childhood vaccines bought for use in public health centers through a national contracting system overseen by the CDC. From 50% to 60% of all vaccines for children are purchased through such arrangements.

By 1998, the price of a dose of tetanus-diphtheria vaccine bought through the government system was 17 cents, says Robert Snyder, who runs the CDC's vaccine purchase program. At the same time, the commercial price for private doctors and non-public agencies was $2 a dose. Some manufacturers stopped selling tetanus-diphtheria vaccine to the government.

'We can't afford to do this'

"The manufacturers said, 'We can't afford to do this under the cap, so we're not going to sell it to you anymore,' " Snyder says. Those vaccines are now purchased through state efforts, but at a negotiated price higher than the federal cap.

Because the law exempts new vaccines, the price caps cover only three vaccines — inactive polio, hemophilus influenzae and measles-mumps-rubella, about one-third of the recommended childhood vaccines, Snyder says.

He calls the caps a two-edged sword. They make it harder for vaccine-makers to stay in the market, but they also help keep the nation's health care tab down. "If they took the cap off, I'd have to pay what I'd have to pay, and I have no idea how high the price would go," says Snyder, whose program spends more than a billion dollars a year buying childhood vaccines for states.

Snyder says there is a need for earlier warning when a vaccine maker is going to get out of the production business. "Had we known 6 months in advance (that Wyeth would stop production of tetanus vaccine), other vaccine-makers could have ramped up sooner," Snyder says. "But the government doesn't control business. It's not the government's responsibility to monitor the way companies do business, unless they're doing something fraudulently."

[Good overview of the problem. Interesting even in the abbreviated list above, how often "manufaturing problems" are mentioned. Also note: I thought the issue of the price caps was a two-edged sword that the manufacturers *agreed to* because they in return received some protection from liability claims related to those vaccines. --Andre]

-- Andre Weltman, M.D. (aweltman@state.pa.us), July 11, 2001