A guidance issued by FDA last week invited the industry to explore limited preclinical testing in humans. In response, some patient groups are criticizing the agency for encouraging companies to speed up drug development. But experts who monitor drug safety and development hailed the directive as a small, but significant, step in bringing more effective treatments to the market.

    By encouraging preclinical human testing, sometimes called “Phase 0,” the agency aims to improve the development process. Phase 0 testing allows researchers to give very small amounts of the compound they are investigating to humans. The doses must be small enough that they do not have any impact on the patient and are given only once or a few times.

The purpose of these studies is to see how the molecule behaves in humans.     For example, they could observe whether it binds to a target receptor or enzyme, or see how the compound is distributed throughout the body.

    This type of research could prevent developers from spending the time and money to continue studying a compound that will not act as expected in humans, said Christopher-Paul Milne, assistant director of the Tufts Center for the Study of Drug Development. For example, the human body’s inability to properly absorb a compound is a common pitfall that stalls many promising compounds in clinical trials, he said. Using Phase 0, this sort of problem could be detected before heading into clinical trials.

    According to FDA, fewer than 10 percent of molecules studied as potential medicines make it far enough for the manufacturers to apply for approval as a new drug.

    Phase 0 testing could also help researchers with  several potential drug candidates determine which one is most likely to work in humans.

    Phase 0 testing should not decrease drug safety, according to Charles Bennett, professor at Northwestern University’s Feinberg School of Medicine and principal investigator of the ongoing Research on Adverse Drug-Events and Reports study, which is conducted with government funding by 25 physicians around the country.

    “I don’t think that this is going to bring more unsafe products to the market,” he said.

    He added that knowing more about how a compound works in humans could provide insights that help researchers maximize the potential drug’s benefits.

    Experts agreed that Phase 0 testing is not an attempt to help developers cut corners.

    “This is an innovation. It’s not a shortcut,” said Raymond Woosley, president of The Critical Path Institute, a non-profit research organization aimed at helping the industry speed up drug development. “It’s a means by which we can use new technology and expand our understanding of medicine.”

    Drug development currently works on a one-size-fits-all model, explained Michael Rosenberg founder and chief executive officer of Health Decisions, a contract research organization.

    “Our model has been broken,” Woosley said.

    Phase 0 testing acknowledges that flexibility is necessary to best understand the potentials of different compounds, Rosenberg added.

If drug development continues to take so long and cost so much money, then personalized medicine will lever be possible, according to Woosley.

    “We’ll need to have to have a lot more medicines to treat different people,” he said. “But if it costs a billon dollars to develop a drug, it’s not going to happen.”

    Using the current system, researchers do not know if a compound they are studying works in humans until the end of a clinical trial, Rosenberg said. But a more flexible approach, such as Phase 0 testing, allows researchers to make decisions at an earlier point.

    “The sooner you can identify problems, the better, “ he said, adding that the industry must embrace the full extent of available technology to improve drug development.

    But Linda Bentley, an attorney at Mintz Levin, who works in  health and biotechnology, is skeptical that Phase 0 testing will produce the desired result. Success in limited human exposure does not mean that the drug candidate will be successful in later phase trials, when most costs are incurred, she said. She added that Phase 0 testing would use healthy individuals, so it would not offer any insight on how the compound will behave in actual patients.

    Milne added that at first, embracing Phase 0 testing could add time and costs to the development process.

    “But if the predictive value is good, that will have paid for itself a few times over,” he said.

    Bentley believes that companies will try to adopt the practices outlined by FDA, but said that the success of the program lies in how well this type of data is received when presented to the agency divisions in charge of different therapy types.

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Observing drug candidates in humans early in the development process could save investigators time and money, experts say.

FDA Encourages Exploratory Human Testing

Prashant Yadav, a professor of supply chain management at the Zaragoza Logistics Center at the University of Zaragoza in Spain, believes the influenza vaccine shortages of recent years are caused by a mismatch of supply and demand. He recently collaborated with the Massachusetts Institute of Technology Center for Transportation and Logistics to conduct a study on improving flu vaccine distribution. The report proposes several solutions for preventing vaccine shortages. PharmExec Direct conducted a short interview with Yadav to learn more about his findings.

I understand that you believe the crux of the problem with vaccine shortages is a supply and demand problem.

Most of the policy decision makers and even people in the pharmaceutical distribution sector assume that the crux of the problem is that we have too little supply. You only have two manufacturers left, so that does remain one of the key problems. But if you look at last year, which was in some sense the worst year in terms of the supply situation, at the end of the year we still had about 5 million doses in excess. So it seems like we have some distribution problems as well. Some people who wanted flu shots last year who did not get them, and at the same time we ended with doses in excess. This means those doses were not placed or distributed in the market according to where the demand was. 

Can you review some of your proposed solutions for dealing with this supply/demand mismatch?

There are two types of demand. One is the elderly and the infantile -- what we call the priority demand. That is more or less predictable. Every practice knows how many people over a certain age or how many children come to them as regulars, and they know that all of those people are going to get a vaccine. The second group is normal adults, who decide whether they are going to get vaccinated primarily based on two things: how bad the previous flu season was and how far flu has spread in the current season. This demand is highly unpredictable, so most doctors end up ordering based on only the first category I mentioned. 

One of our key recommendations is some kind of information portal where physicians or officer managers could look up information on how supplies are distributed geographically and then use that to redistribute.  This is something the Centers for Disease Control are already working on. 

Another thing that hasn’t been explored to its fullest yet, is a buyback mechanism. This could make doctors order greater quantities than they do now, because they would not fear getting stuck with excess at the end of the season. But the ability to return vaccines unconditionally could encourage doctors to over-order and send vaccine back at the end of the season. A conditional buyback, where you can return up to 50 percent of the stock that you bought initially, would incentivize physicians to do a better job forecasting demand. 

Another of the suggestions in your report was giving healthcare providers, physicians, and office managers better tools to estimate the vaccines they would need. Can you elaborate a little more on what kind of tools those would be and how they would work?

This goes back to our observation that most healthcare providers buy vaccine based on gut feeling -- they have no scientific method. We suggested a system that keeps track of how many doses they ordered one year, and who they were administered to, and projects how many doses they are going to need the next year.  This could be a desktop tool, which would be provided to all physicians’ offices. Every time they administer a vaccine, they would enter this information. The next year, before they start preordering from the manufacturer or from a distributor, they can use this very tool to give them recommendations.

And who would develop or manage this tool? Would it be the government, the vaccine manufactures, or some other group?

Some of the forecasting models would have to come from data CDC collects on a weekly and a monthly basis about the onset of flu, along with internal data recorded by the physician’s practices. The two need to be coupled together to create a more robust forecasting model. Each of the healthcare providers could use it, and it could be customized to their geographic region or their clientele – demographics, how many people are insured, things like that. 

When thinking about flu vaccine supply chain issues, are there any other industries that can be used as a guide for physicians or manufacturers? Is there anything comparable?

There is the question of perishability in a lot of pharmaceutical products. But for flu vaccines it is more than a shelf life issue. At the end of the season, this product is of zero value, because we switch the strains after every season. So, the average yield of production is lower than you would observe in most pharmaceutical manufacturing, in fact in most manufacturing in general, because if the batch has been used, that’s all there is. At the same time, the market does not determine the price. The price is preset and the demand is uncertain. 

In most markets, depending on the demand and supply situation, the market would adjust and create a price. But in flu vaccines that’s not the case. I would argue that flu vaccines are commodities. Companies use identical strains, and more or less the same manufacturing process, so the product that comes out is more or less like a commodity. 

One comparison would be crops. I’m based in Spain, so I will look at Spanish olives. The market here has high yield uncertainty -- sometimes the crop completely fails, sometimes you have a bumper harvest. But for olives, the price is set by supply and demand. For some agricultural commodities, Florida oranges for example, the government comes in and looks at the supply and demand situation and sets a fair price, or at least they used to set a fair price once upon a time. 

But there is not a comparable industry, because of the many different sources of uncertainty and the inability to freely set the price. We thought about what would this best compare to, or where could we benchmark this with, and we were not able to find anything that was close enough.

Q&A with supply chain expert Prashant Yadav, lead investigator on a study of how to improve flu vaccine distribution.

Understanding Demand, Not Just Supply, Key to Solving Flu Vaccine Shortages

In an attempt to cut down on counterfeiting, Pfizer added 13.56megahertz radio frequency identification (RFID) tags to all Viagra (sildenafil) labels earlier this month. The company has also tagged shipping cases and pallets. 

    Using this emerging technology for such a popular product is an important step towards embracing tools that many believe will soon be nearly universal. Others say it is crucial for ensuring the quality of a popular drug that is often counterfeited.

    “I think this is a wonderful idea because Viagra is one of the drugs that is most frequently and prolifically counterfeited,” said Michael Patton, executive director of the Illinois Pharmacists Association. “It’s a plus on behalf of pharmacies and on behalf of healthcare for all patients.”

    Pharmacies and wholesalers can scan the labeled pallets and cases when they receive a shipment, provided they have the scanning technology. The Viagra RFID program will not track the shipment through every step of the supply chain, just its delivery at a distribution center. This will allow the recipients to ensure the Viagra they receive is not counterfeit, said John Jordon, president of worldwide field operations at Tagsys, the company providing the RFID technology for the labels.

    Pfizer said it would consider taking the technology further, to a track-and-trace program. According to John Cronin, senior vice president and counsel for the California Pharmacists Association, track-and-trace is the ultimate goal of using RFID for drugs.

    According to Pfizer, the technology cost several million dollars to implement.

    The RFID tags for Viagra labels work by the same mechanisms as passes that allow cars to drive through tollbooths without stopping, Jordon said. The tags contain circuitry that is activated when it is close to a corresponding antenna. Once it is “woken up,” the tag communicates a number to the antenna, which relays it to a computerized database, where the number is verified.

    These readers can cost hundreds to thousands of dollars, Jordan said. But he added that each facility would only need one reader at first.

Jordon and Patton agreed that the price of this technology would probably decrease as RFID tagging becomes more common.

    Pharmacists believe embracing this technology is inevitable. Jordon predicted that it would take off over the next five years, with mass adoption starting in 2008. It is starting with products that are often stolen, abused or counterfeited, he said. But after many of the high-risk drugs are verified using RFID, the technology will be common and inexpensive enough that nearly all branded drugs and over-the-counter products could use RFID tags.

    “Anything of reasonable value would then likely have a tag,” he said.

Right now, reading shipments with RFID technology is more useful for pharmaceutical wholesalers than pharmacists, Cronin said. But he predicted that it will eventually be implemented everywhere.

    “This is the first step down a road that we’re all going to have to go down eventually,” he said.

Learn how RFID technology works and what it could mean for pharmacies down the road.

Pharmaceutical Executive-01-17-2006

FDA Encourages Exploratory Human Testing

Understanding Demand, Not Just Supply, Key to Solving Flu Vaccine Shortages

Pfizer Adds Radio Frequency Identification Tags to Viagra