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By: FoxChase1803
01 Feb 2004, 08:34 AM EST
Msg. 137324 of 137402
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Interesting article: The two-headed beast

Phase I/IIa. Phase IIa. Phase IIb. Phase IIb/III. It's a jungle of clinical trial terminology out there. The biotechnology sector, once intent on catapulting drug candidates through early studies to Phase III trials, has slowed down -- at least semantically -- to linger over Phase II studies. Properly conducted, Phase IIs may offer industry the chance to reduce risk and increase efficiency by dispensing with weak product candidates. Biotech companies have taken to using "Phase IIa" and "Phase IIb" to describe these crucial trials but the practice has been more art than science, utilized with no regulatory sanction.

New data from more than 100 clinical trials in Recombinant Capital's database show that Phase IIa and Phase IIb trials really are different beasts in terms of size, scope and rigor of design. Yet our data also suggest that there's little evidence these studies are efficiently weeding out mediocre drugs. Meanwhile, FDA officials lament the reported 50% failure rate of Phase III trials and are scrutinizing pre-Phase III development programs. As a result, the agency has initiated a pilot program for a new "End-of-Phase-2A" Meeting -- with the hope of improving the design and conduct of both Phase IIb and Phase III trials and, ultimately, the quality of NDAs and BLAs.

The metastasizing terminology used to describe clinical trials of late, from Phase Ic (yes, it's true) to Phase IIb/III, has blown apart the tidy Phase I-Phase II-Phase III succession that has long aided the layperson's understanding of drug development. Once upon a time, Phase I meant safety studies in healthy volunteers, Phase II meant safety and dosing studies in a targeted patient population and Phase III meant large-scale safety and efficacy trials. Those comfortingly simple labels have been replaced by an array of official-sounding clinical trial terms that can be confusing to patients, investors and analysts alike.

The breakdown began with "Phase I/II" and "Phase II/III" trials, clear semantic nods to the overlapping, parallel nature of the work needed to prove a drug's benefit. But the proliferation of new terms continued. It appears to have progressed most acutely among biotechnology companies in the description of Phase II trials, which are now routinely referred to as Phase IIa or Phase IIb, along with their inscrutable counterparts, Phase I/IIa and Phase IIb/III.

It could be that smaller companies are finally realizing what large pharmaceutical concerns have known for a long time -- that Phase II trials are the muddy trenches of drug development where the battle is most likely won, or lost. It's in Phase II trials that crucial knowledge is gathered about how a drug behaves in a target patient population in terms of its toxicity profile, its mechanism of action (or lack thereof) and the doses and/or regimens needed to produce that action. Go-no go decisions after high quality Phase II programs should allow companies to invest or redirect resources efficiently.

"Companies that are good at drug development have always recognized that Phase II is the critical place to weed out drugs that don't have a good future in terms of safety or efficacy," said John Jenkins, director of the Office of New Drugs at the FDA's Center for Drug Evaluation and Research (CDER).

A former FDA official who asked not to be identified put it more bluntly. "The rush to Phase III trials by biotechnology companies wasted billions and billions of dollars," he told Signals. "Small molecules developed a solid paradigm for evaluating drugs in humans and the idea that biologics were somehow safer and more effective and didn't have to go through solid clinical work was absurd."

Gobbledegook… or not

Skeptics argue the new Phase II descriptive terms used by biotechs are just more of the same old "phase inflation" long employed by smaller companies to woo Wall Street. Back in 1998, Bobby Sandage, Jr., executive VP of research and development at Indevus Pharmaceuticals Inc. (formerly Interneuron Pharmaceuticals Inc.) wrote that the terms Phase IIa and Phase IIb were "specific jargon" invented by industry. (Balancing Phase II and III Efficacy Trials, Bobby W. Sandage, Jr., Drug Information Journal, Vol. 32, pp. 977-980.)

"In the past there was an effort to gently nudge things verbally to add a phase advancement impression," explained Sandage recently. "But the terminology doesn't help us any, it doesn't change the actual process."

At the heart of that process, according to Sandage, is establishing an effective dose range and regimen. "Phase II doesn't need to be long and complicated, but it does need to be complete," he said. "You've got to know the magnitude of response for design of the Phase III trial." Indevus doesn't use the Phase IIa and Phase IIb monikers to describe its trials, but Sandage told Signals he believes that the labels are here to stay. "Over the last 10 years it has evolved as a way to describe to investors and analysts with more precision where a drug is in the development process," he said. "Even the FDA may one day adopt it with formal definitions."

The FDA's Jenkins insists there is no official definition of Phase IIa, Phase IIb or even plain old Phase I, Phase II, and Phase III trials. He did explain that, generally speaking, early Phase II -- or Phase IIa -- studies look at the absorption, metabolism and pharmacodynamics of a drug rather than at clinical benefit or safety. The second stage of Phase II development -- so-called Phase IIb studies -- "will look more like Phase III trials" because they are looking for clear indications of clinical efficacy and safety in larger groups of patients.

"The labels are very much terms of art and not well defined," cautioned Jenkins. "A lot of biotech companies use [Phase IIa and Phase IIb terminology] more from a marketing perspective than any regulatory meaning. Trying to exactly characterize these trials is more hype than anything else… companies make too much out of it."

A matter of definition

What's in a name? that which we call a rose
By any other name would smell as sweet;
-- William Shakespeare

So, what exactly is a Phase IIa trial or a Phase IIb trial? Hype or no hype, Signals set out to answer that question by using Recombinant Capital Inc.'s (ReCap) clinical trials database as a starting point. ReCap focuses mainly on therapeutics being developed by biotechnology firms, alone or through partnerships; as a result, our data may not reflect what might be typical of large pharmaceutical companies in conducting Phase II trials. We sequentially selected a total of 111 self-described Phase IIa and Phase IIb clinical trials for which relevant data points were obtainable. "Self-described" includes any trial which at some point during its planning, initiation, conduct, completion and reporting had been described by its developer (or a corporate partner or acquirer of its developer) using the exact phrase "Phase IIa" (or "Phase 2a") or "Phase IIb" (or "Phase 2b").

We compiled data on 68 Phase IIa trials and 43 Phase IIb trials for a total of 111 trials. As might be expected, we found that Phase IIa trials were smaller than Phase IIb trials: Phase IIa trials enrolled an average of 90 patients at 10 sites while Phase IIb trials enrolled an average of 275 patients at 33 sites. Less predictably, we found that both types of trials tested the same average number of doses -- just two.

For statistics buffs, we ran a statistical test called an Analysis of Variants (or ANOVA) in order to gauge the probability that the differences we observed between these two types of trials were due to chance alone. (Statistical analyses of ReCap's data were provided courtesy of Steven Banks, Ph.D.) We found that the differences in size and scope of these trials are highly statistically significant (p=0.0001), which means there's only one chance in 10,000 that they aren't real. Based on these data, it's probably fair to assert that companies in this group who say they are running a Phase IIa trial or a Phase IIb trial are running markedly different studies, in terms of the number of patients enrolled and number of sites utilized. (see Graph #1). For a link to the data used as a basis for our findings on Phase IIa and Phase IIb trials, click here.

Graph 1: The difference in average number of patients enrolled between Phase IIa trials (89.9 patients) and Phase IIb trials (275.2 patients) is statistically significant (p=0.0001, ANOVA). Likewise, the difference in average number of sites involved (9.8 vs. 32.6) is significant (p=0.0001, ANOVA). The average number of doses evaluated (2) is the same for both types of trials (p=NS).

Phase IIa and Phase IIb trials from our database also differed in terms of scientific rigor of design. The gold standard for clinical trials is a randomized, double-blinded, placebo-controlled study. Assigning patients randomly to receive the different treatments in a trial, "blinding" or concealing those treatments from the investigators and health care workers running that trial and comparing experimental treatments to a control or baseline group are all measures which work together to assure that data from a clinical trial is less skewed in one direction or another.

"There are no particular standards for optimal study design of Phase II trials," insisted the FDA's Jenkins. But, he added, clinical trial design is better served with randomization and controls because "it's easier to interpret controlled data." Carl Peck, Director of Georgetown University's Center for Drug Development Science (CDDS), goes farther: "Let me make a blanket statement here and say that every clinical trial in a new drug development program should be double-blinded, randomized, and placebo-controlled and should evaluate multiple active doses unless there is a highly compelling impediment or reason not to. I don't know what would motivate anybody to do substandard science."

Applying the Gold Standard

In our group of 111 Phase IIa and Phase IIb trials, a majority of all the trials were rigorously designed, though the Phase IIa trials fell far short of Peck's 100% standard. Of the 68 Phase IIa trials, 72% were randomized, 66% were blinded and 73% were controlled. Of the 43 Phase IIb trials, 95% were randomized, 74% were blinded and 95% were controlled. The difference in percent of trials randomized between Phase IIa (72%) and Phase IIb (95%) trials was statistically significant (p=0.003, using another statistical test called the Fisher Exact test, which is more appropriate for this type of data). Likewise, the difference in percent of trials that were controlled between Phase IIa (73%) and Phase IIb (95%) trials was significant (p=0.004, Fisher Exact Test). However, about the same percentage of Phase IIa trials (66%) and Phase IIb trials (74%) were blinded (p=not significant or NS) (see Graph #2).

To be fair, it may not be easy to blind clinical trials in some indications, particularly cancer. Nineteen of the 68 Phase IIa trials (that's 28%) in our group were neither randomized, blinded nor controlled, representing the least rigorous design possible. Of those 19, 12 were in cancer indications (three were in cystic fibrosis, another problematic setting). Although he did not review ReCap's data specifically, Peck maintains that, generally speaking, companies often don't want to go to the trouble of blinding all studies because it adds time and expense to the conduct of trials. While he acknowledged that blinding was impossible in some "rare oncology settings," Peck argued, "most of the time when companies claim they can't do it, it's because they don't want to do it. Money and inexperience are part of it." He ought to know: Under Peck's leadership, Georgetown's CDDS has been involved in more than 225 IND programs with more than 80 companies since its inception in 1994. It has active research, public policy, technical assistance and consulting programs with industry ongoing.

Full steam ahead

If you torture the data long enough, [it] will always confess.
-- Ronald Coase, 1991 Nobel Prize for Economic Sciences

We also recorded the percentage of Phase IIa and IIb trials that produced statistically significant results and the percentage of those trials that resulted in a product's advancement to the next stage of development or in termination. A trial was graded SS (Statistically Significant) if a p-value of less than 0.05 was reported for a primary prospectively defined endpoint or if the results were characterized with the exact phrase "statistically significant," even if no p-value was disclosed. A trial was graded NS (Not Significant) if it did not achieve statistical significance as defined above. A trial was graded A (for Advance) if its development was furthered by the sponsoring company, either in the form of further Phase IIa trials, advancement to Phase IIb trials or advancement to Phase IIb/III, Phase II/III or Phase III trials, as applicable. A trial was graded T (for Termination) if development ceased following the given clinical trial, for any reason. For both these designations, data were missing and/or simply unobtainable for some trials and some trials are still ongoing.

Since many Phase IIa trials are not "powered" (meaning not big enough) to produce statistical results, the lack of statistical significance may have limited meaning. Nonetheless, our data show that both types of trials produced statistically significant results at a substantial rate, 53% for Phase IIa trials and 45% for Phase IIb trials (p=NS, meaning that there was no significant difference in these two rates). Both types of trials had similar advancement rates also, with 77% of drugs advancing beyond Phase IIa trials and 64% of drugs advancing beyond Phase IIb trials (p=NS).

Graph 2: The difference in percentage of trials that were Randomized between Phase IIa trials (72.1%) and Phase IIb trials (95.2%) is statistically significant (p=0.003, Fisher Exact Test). The difference in percentage of trials that were Blinded (66.2% vs. 73.8%) is not significant. The difference in percentage of trials that were Controlled (73.5% vs. 95.4%) is significant (p=0.004, Fisher Exact Test).

For a link to the data used as a basis for our findings on Phase IIa and Phase IIb trials, click here.

It's not clear why so many drugs perform so well in Phase IIa and Phase IIb trials. Further, even if they don't perform well, their forward progress is not impeded. This disconnect may be one area worth studying further. Experts say that weak drugs should be weeded out during the Phase II stage of development but our data show that, in this group at least, a hefty majority of drugs sailed on through (see Graph #3).

To explore this phenomenon more fully, we compared the advancement rates of the least rigorously designed (either not randomized or not blinded) Phase IIa and Phase IIb trials to those of the most rigorously designed (randomized and blinded). Although the numbers were small (due to missing or incomplete data), we found that, once again, drugs marched through Phase II trials regardless of design rigor. Drug candidates in rigorously designed Phase IIa trials proceeded 73% of the time. Interestingly, drugs tested in the least rigorous Phase IIa trials advanced at a significantly higher rate (85%) than those tested in the least rigorous Phase IIb trials (25%) (p=0.05, analyzed using the Breslow-Day test, which applies best here).

The puzzling take-home message to Phase IIa drug candidates seems to be: "If your trial is rigorously designed, you'll advance! And if your trial is less rigorously designed, even more of you will advance!" Any way you dice it, most drugs that began Phase IIa testing in our sample moved forward, regardless of the circumstances. Drugs tested in rigorously designed Phase IIb trials also advanced at a high rate (71%). However, we have little data with which to draw conclusions about less rigorously designed Phase IIb trials (see table).

To go or not to go

The question arises, is the forward momentum of these product candidates driven by data, design or delusion?

Despite significant differences in size and rigor, Phase IIa and Phase IIb trials in our sample produced no difference in terms of advancement outcomes. Our data raise the possibility that, despite increased investment and sophistication in the conduct of Phase II trials, drug development decisions may not be better informed.

"The level of excitement about clinical data should not be determined by labels like Phase IIa or Phase IIb or even Phase III, but rather by the rigor of design," said David Stump, SVP of drug development at Human Genome Sciences Inc. in Rockville, MD. "That means appropriate controls, blinding, randomization, adequate powering and meaningful clinical endpoints producing a clinical result which is highly significant."

Stump, who spent 10 years at Genentech Inc. before joining HGS, presides over his company's clinical development program -- which routinely uses the Phase IIa and Phase IIb nomenclature to describe early- and later-stage trials. HGS tends to run rigorously designed trials. For example, in ReCap's sample of HGS-sponsored Phase IIa trials in four different indications, all were randomized, blinded and controlled. The company has been quick to terminate products that don't perform well in these trials -- it recently dropped both mirostipen for chemotherapy-induced neutropenia and repifermin for ulcerative colitis when they stumbled in Phase IIa studies.

"If you are in a situation where you have many product opportunities, which is exactly what we have here at Human Genome Sciences, the real critical factor for achieving business success is identifying winners clearly and quickly," said Stump. "The key incremental knowledge about the likelihood of success of a product really comes at the end of a robust Phase II trial. We try to work efficiently to get a clear go/no go answer at the end of Phase IIs."

Top ten reasons why you flubbed your phase II trials
Drug development experts and regulators continue to grapple with what many consider an unacceptably low success rate for Phase III trials. According to Georgetown's Peck, while the average Phase III trial success rate is around 70%, that figure is heavily weighted by results from "antibiotics and 'me-too' drug trials." Actual success rates plummet when you look at, say, neurological disorders -- where only 15% of drugs tested in late-stage trials succeed -- or at cancer drugs, where the success rate is about 20%, by Peck's estimates. "This suggests a poor pre-Phase III clinical trial program, unable to provide the information necessary to undertake successful Phase III trials," said Peck. "A Phase III trial should have a 90% chance of being successful."

Internal FDA estimates put the overall success rate in Phase III trials at about 50% (meaning half of all Phase III trials fail), according to Lawrence Lesko, director of the office of clinical pharmacology and biopharmaceutics at CDER. "We don't know what the underlying reasons for the high failure rate in Phase III trials are," Lesko lamented at a Nov. 17 meeting of the FDA's Advisory Committee for Pharmaceutical Science (ACPS).

Naturally, the spotlight has gradually been shifting backwards from Phase III trials to Phase II development work. Typical Phase II blunders include designing and conducting non-rigorous trials (see discussion above), using endpoints that are well-reasoned biomarkers but have no clinical relevance, conducting trials on too small a scale for interpretability, and over-interpreting weak data. But a consensus may be emerging -- at least at the FDA -- about the top culprit in flawed Phase II clinical programs (drum roll, please) and that is… inadequate exposure-response work. It's the Phase II trial design twist on that age-old real estate maxim: dosing, dosing, dosing. Or, for those who prefer political campaign analogies, "It's the dose-response data, stupid!"

Graph 3: Phase IIa and Phase IIb trials produced statistically significant results at roughly the same rate (53% vs. 45%, p=NS). Likewise, drugs tested in Phase IIa and Phase IIb trials advanced to the next phase of development at roughly the same rate (77% vs. 64%, p=NS).

(1) A trial was graded SS (Statistically Significant) if a p-value of less than 0.05 was reported for a primary prospectively defined endpoint or if the results were characterized with the exact phrase "statistically significant" even if no p-value was disclosed. A trial was graded NS (Not Significant) if it did not achieve statistical significance as defined above. Data were missing and/or simply unobtainable for some trials and some trials are still ongoing: N values inside the bars reflect this. (2) A trial was graded A (for Advance) if its development was furthered by the sponsoring company, either in the form of further Phase IIa trials, advancement to Phase IIb trials or advancement to Phase IIb/III, Phase II/III or Phase III trials, as applicable. A trial was graded T (for Termination) if development ceased following the clinical trial, for any reason. Data were missing and/or simply unobtainable for some trials and some trials are still ongoing: N values inside the bars reflect this.

For a link to the data used as a basis for our findings on Phase IIa and Phase IIb trials, click here.

"One of the biggest mistakes made in Phase II development is not taking the time to select the right dose and dosing interval to take into Phase III," observed the FDA's Jenkins. "If you move into Phase III trials and a drug shows no efficacy or a safety problem arises, it probably could have been anticipated if the sponsoring company had done its Phase II homework. If they'd actually taken the time to select a more appropriate dose, the drug may have actually worked."

As criticism of the FDA's review times reached a roar in 2002 (to see the Signals article "Ghost in the Machine" on that topic, click here), the agency has sought to explain its multiple review cycles of NDAs. At the November 2003 ACPS meeting, results of a retrospective "informal study" of 10 NDAs from 2002-2003 that underwent multiple review cycles (rather than being approved on the first try) were reported. Peter Lee, associate director of pharmacometrics at OCPB, said dose selection strategy was a stumbling block in all cases studied. "Sub-optimum doses selected in NDAs that were reviewed led to lack of efficacy, toxicity problems and lengthened review times," he said.

Learning vs confirming

Academics have been aware of the dosing issue for some time now. For example, Lewis Sheiner, professor of laboratory medicine, biopharmaceutical sciences, and medicine at the University of California, San Francisco, has been developing mathematical models and data analysis techniques to enable valid predictions of dose-exposure-response obtained from in vivo observations, especially those made in clinical trials, or in the course of routine patient care. In a 1997 paper lauded by Peck and others, Sheiner advocates a decreased focus on confirming (demonstrating efficacy) and an increased focus on learning (science) in clinical drug development. (Learning Vs. Confirming in Clinical Drug Development, Lewis B. Sheiner, Clin Pharmacol Ther, 1997 Mar, 61 (3):275-91.)

"Doing more than lip-service to the importance of science (learning) in contrast to empiricism (confirming) in drug development will require a major paradigm shift for the pharmaceutical industry," Sheiner wrote. "It will require not only new tools (e.g., computer software for the dosing and analysis of scientific studies), but a radical change in the structure of pharmaceutical pre-clinical and clinical R&D units: a reorientation of thinking cannot be accomplished without a reorientation of process."

Such a reorientation may be difficult for the smaller biotechs like those in ReCap's universe of companies. Even high quality Phase II programs, such as those conducted by HGS and other biotechs, pale in comparison to the extent of Phase II work undertaken by big pharmaceutical companies. Georgetown's Peck, who served at the FDA as director of CDER from 1987 to 1993, said that some larger companies conduct 5 to 20 Phase II trials. For instance, of the approximately 70 protocol-based trials in the Viagra NDA, he told Signals, at least 30 were Phase II studies. And he is aware of at least one NDA that contained more than 600 trials.

"The deep pockets take a redundant, exhaustive approach," said Peck. "On the other side you've got biotech companies who attempt an early, first-in-human trial, then jump to a Phase II/III trial and, if it looks good they call it Phase III but if it doesn't look good they call it Phase II. It sort of skirts the process of learning about the drug." There is a middle ground, according to Peck, where smart companies can optimize the value of Phase II trials by making them part of an integrated development program where every trial counts.

"No trial should be irrelevant," explained Peck. "Your Phase II proof-of-concept and dose-optimization studies should be designed to provide at least part of the evidentiary database for licensure and they should always provide good learning, not just confirming." Dosing studies of the type the FDA is advocating are weighted to the learning side of the learning-confirming continuum.

In Sheiner's view, one immediate practical application of the learn-confirm approach is that "scientists must have the major responsibility for planning and analyzing, if not executing, phase 2B [trials]." It seems the FDA has been listening.

The FDA rides to the rescue

At the November ACPS meeting, CDER's Lesko said the agency is concerned by internal estimates that show NDAs for new molecular entities plummeted from a high of 50 in 1995 to around 20 in 2002. Further, INDs are at a record low. "We are asking ourselves what problems need solving in this current environment for new drug development," said Lesko in his opening remarks. Shortly thereafter, he debuted the agency's proposal for the tongue-twisting End-of-Phase-2A Meeting (nicknamed EOP-2A). As Lesko tells it, this pilot program, which will allow up to two sponsors per month to apply for and receive an EOP-2A meeting with FDA staff, is a direct result of FDA commissioner Mark McClellan's Strategic Action Plan, unveiled in August.

McClellan's manifesto calls for "science-based efficient risk management" at the agency so that drug development will be less risky, more predictable, and faster. The agency has hypothesized that meeting with companies early in the Phase II stage of development will foster better analyses of dose response information and will aid in dose selection and study design for later trials. In short, the FDA wants to try its hand at helping design Phase IIb trials.

Currently, the agency has formal meetings with sponsors prior to an IND filing (to review the preclinical data) and at the end of Phase II, immediately prior to the start of Phase III trials, plans for which have already been cast in stone at that point. "That's kind of too late," observed Jenkins. He said the EOP-2A pilot program is FDA's attempt to interact with companies at a time that makes more sense -- before definitive dose-ranging studies have been initiated and before planning for Phase III trials has begun. The meetings will be voluntary, informal and interdisciplinary.

The October 2003 Concept Paper introducing the EOP-2A Meeting pilot program states that "EOP-2A occurs following the completion of phase 1 and the first set of exposure-response studies in patients, and before beginning phase 2b and phase 3 studies."

"We are trying to fill the gap between the pre-IND meeting and the End-of-Phase 2 meeting and to keep the company from making costly mistakes," explained Jenkins. "We think the [EOP-2A] meeting will add a lot of value to the drug development process. The problem for us and the reason it's a pilot program is that it will require hundreds of hours of preparation on the FDA staff side."

Table: Percent Of Phase IIa And Phase IIb Product Candidates Advancing To Later-Stage Trials, Categorized By Rigor of Trial Design

Less Rigorous Design

(Either Not Randomized Or Not Blinded) More Rigorous Design
(Randomized And Blinded)
Self-Described Phase IIa Trials 12/14 - 85% 28/38 - 73%
Self-Described Phase IIb Trials 1/4 - 25% 15/21 - 71%

The difference in advancement rates between less rigorous Phase IIa trials (85%) and less rigorous Phase IIb trials (25%) is significantly greater (p=0.05, Breslow-Day Test) than more rigorous studies, which advanced at roughly the same rates in Phase IIa trials (73%) and Phase IIb trials (71%).

For a link to the data used as a basis for our findings on Phase IIa and Phase IIb trials, click here.

"The FDA is not trying to make Phase II longer or more complex or more costly," Jenkins noted. "But we think we can have an impact by meeting with companies earlier. We now have a small cadre of staff who are expert in early study design." A draft guidance on EOP-2A to be published next year will reveal the criteria by which applicants for the meeting will be judged. "At the end of the day, the FDA will have to make decisions about which companies are most committed to this process, " said Jenkins. "A pilot program gives us the ability to focus on programs where we can make the most difference."

At the November ACPS meeting, FDA consultants, including Sheiner himself, reviewed the EOP-2A proposal and endorsed it, although not without skepticism. "What is the reason that those smart people in the pharmaceutical industry are not looking at this stuff already? It's not because they're not smart," said Sheiner at the meeting. "There must be institutional reasons why it's not happening."

"I'm concerned that this could be another piece of red tape, another hurdle to jump through for companies," said David Flockhart, chief of the division of clinical pharmacology at the Indiana University School of Medicine. "The same regulatory system was in place when NDAs were going up in 1995 as is in place now when they are going down. Are there any better alternatives than a new meeting?"

In the end, ACPS panel members seemed to agree that no harm could come from the EOP-2A proposal, except in terms of the cost, time and effort expended by the FDA itself. If one views Phase II trials as a drug company's homework, then even the brightest students may need parental supervision to do a thorough job. UCSF's Sheiner summed it up best when he said of the EOP-2A proposal, "I think it's a good idea, but I'm not exactly sure why."

The unanswered question lurking here is the following: Will FDA involvement in Phase II dose-response testing lead to more drugs with better NDA or BLA packages or will it lead to higher Phase II termination rates? Either outcome could contribute positively to efficient drug development.

By: FoxChase1803
01 Feb 2004, 09:59 AM EST
Msg. 137327 of 137402
Jump to msg. #  
Making Drugs, Shaping the Rules

NYTimes, February 1, 2004

THE drug industry has created vast markets for products like Viagra, Celebrex and Vioxx by spending billions of dollars on consumer advertising.

But to sell medicines that treat schizophrenia, the companies focus on a much smaller group of customers: state officials who oversee treatment for many people with serious mental illness. Those patients - in mental hospitals, at mental health clinics and on Medicaid - make states among the largest buyers of antipsychotic drugs.

For Big Pharma, success in the halls of government has required a different set of marketing tactics. Since the mid-1990's, a group of drug companies, led by Johnson & Johnson, has campaigned to convince state officials that a new generation of drugs - with names like Risperdal, Zyprexa and Seroquel - is superior to older and much cheaper antipsychotics like Haldol. The campaign has led a dozen states to adopt guidelines for treating schizophrenia that make it hard for doctors to prescribe anything but the new drugs. That, in turn, has helped transform the new medicines into blockbusters.

Ten drug companies chipped in to help underwrite the initial effort by Texas state officials to develop the guidelines. Then, to spread the word, Johnson & Johnson, Pfizer and possibly other companies paid for meetings around the country at which officials from various states were urged to follow the lead of Texas, according to documents and interviews that are part of a lawsuit and an investigation in Pennsylvania.

How did this play out? In May 2001, as Pennsylvania was weighing whether to adopt the Texas guidelines, Janssen Pharmaceutica, a Johnson & Johnson subsidiary that sells Risperdal, paid $4,000 to fly two state mental health officials to New Orleans, where they dined at an elegant Creole restaurant in the French Quarter, visited the aquarium and met with company executives and Texas officials, according to documents. Janssen also paid two Pennsylvania officials $2,000 each for giving speeches at company-sponsored educational seminars for doctors and nurses working in the state's prisons.

The payments were discovered a little more than a year ago by Allen L. Jones, an investigator in the inspector general's office in Pennsylvania, who stumbled upon them when he was looking into why state officials had set up a bank account to collect grants from pharmaceutical companies.

With the help of his congressman in Pennsylvania, Mr. Jones, who is 49 and a former parole officer, brought the information to the attention of federal health officials - after, he says, his superiors removed him from the investigation, citing the political influence of the drug industry. The Department of Health and Human Services has asked the health care fraud unit of the Federal Bureau of Investigation to determine whether any laws were broken, according to letters Mr. Jones has received from federal officials.

DETAILS of the drug companies' efforts, recorded in Mr. Jones's investigative files and confirmed in part by drug companies and state officials, offer a glimpse inside the drug industry's behind-the-scenes efforts to promote the new-generation antipsychotics, called atypicals because their action in the body is unlike that of earlier drugs.

There is no proof that drug-industry money changed any state official's opinion about the drugs. And compared with the billions of dollars spent marketing to doctors from their first days as medical students - or the billions spent to underwrite and publish research - the dollar amounts are small.

But questions have multiplied about the many ways that the drug industry tries to influence the medical information that determines its products' success or failure.
Last month, for example, some senators sharply criticized the National Institutes of Health for allowing its scientists to accept consulting fees and stock options from drug and biotechnology companies. Officials of the agency said that its top-level scientists were no longer accepting such compensation.

Sales of the new antipsychotics totaled $6.5 billion last year, according to an estimate by Richard T. Evans, an analyst at Sanford C. Bernstein & Company. About a third of those sales were to state Medicaid programs, whose costs have ballooned with their adoption of the new medications. Texas, for example, says it spends about $3,000 a year, on average, for each patient on the new drugs, versus the $250 it spent on older medications. The escalating costs have prompted a few states to try to limit access to the new antipsychotics - efforts that drug makers have opposed vigorously.

The Texas guidelines advise doctors to choose Risperdal or one of four other new antipsychotics - Zyprexa from Eli Lilly, Seroquel from AstraZeneca, Geodon from Pfizer or Abilify from Bristol-Myers Squibb - unless they can explain in writing why an older drug would be better. If a patient does poorly on the first medication, doctors at state hospitals and mental health clinics are advised to try another of the new drugs next. Texas officials said such guidelines were simply a road map for doctors, who can explain to the state on written forms why they are not prescribing a recommended drug.

The drug companies deny doing anything untoward.
They say it was appropriate for them to help pay for the development of guidelines aimed at giving patients the best care. The ones for schizophrenia, they say, were written by medical experts and Texas officials without industry interference.

"Janssen did not participate in nor influence the content or the development of the guidelines,'' said Doug Arbesfeld, a spokesman for Janssen Pharmaceutica. Officials in some states asked the company for financial grants so that they could learn about the guidelines, he said.

Dr. Steven P. Shon, who as medical director of the Texas mental health department led the work on the guidelines, said the effort was not the drug companies' idea. Rather, he said, state officials decided that guidelines were needed because of the wide variations in prescriptions being written for patients.

Dr. Shon said that the condition of many patients had improved when their care followed the guidelines. Even without them, he added, doctors in Texas would have prescribed the new drugs. "Everyone wants to use the new thing,'' he said.

WHEN work on the Texas guidelines began in 1995, only two of the new-generation drugs were approved for sale: Risperdal and Clozaril, a medicine from Novartis that doctors were uncomfortable prescribing because of its known potential to cause a life-threatening blood disorder.

At the time, Janssen had little research on which to base its claims that Risperdal represented a medical advance. In fact, when federal regulators approved the drug, they forbade the company from claiming in marketing materials that it was better than the older drugs.

Now, doctors widely prefer the new medications, saying that the older drugs cause a higher incidence of side effects like stiffness, trembling and uncontrollable jerks that can stigmatize patients and prompt them to stop taking the drugs.

But some recent studies have complicated the picture for doctors by showing that the new medicines have potentially serious side effects, too, including the development of diabetes in some patients.
On Tuesday, four medical groups, including the American Psychiatric Association, warned that the new drugs could increase a patient's risk of obesity, diabetes and high cholesterol - which can all lead to heart disease. Some leading experts on schizophrenia, after reviewing the accumulated scientific evidence, have developed a set of guidelines that clash with the Texas policy. These recommendations, produced entirely with federal government financing, say that physicians should not consistently choose the new drugs over the older medications.

"You choose the one that seems the best for the patient," said Dr. Anthony F. Lehman, the chairman of the psychiatry department at the University of Maryland School of Medicine. Dr. Lehman was the leader of the panel, called the Patient Outcomes Research Team, that put together the alternate guidelines under a grant from the National Institute of Mental Health. The guidelines are expected to be published this spring.

As early as 1999, physicians were raising questions about the drug industry's financing of the Texas guidelines. In an article that year in The Journal of Practical Psychiatry and Behavioral Health, Dr. Peter J. Weiden and Dr. Lisa Dixon argued that corporate financing created a potential conflict of interest that could hurt the project's credibility.

Dr. Weiden, professor of psychiatry at the State University of New York Downstate Medical Center in Brooklyn, said in an interview last month that he believes the new drugs have benefits over the older ones. But he continues to worry, he said, that the industry controls too much of what doctors learn in psychiatry. For example, Dr. Weiden said, industry-sponsored educational events focus on medications, while subjects like how to talk to patients to motivate them to get better fall through the cracks.

"The industry drives education right now," Dr. Weiden said. "Across the board, there has been a shifting of education toward psychopharma," meaning drug treatment.

Mr. Arbesfeld, the Janssen spokesman, said that the company disagreed with the recommendations of Dr. Lehman's panel. A growing body of evidence, Mr. Arbesfeld said, shows the benefits of the new drugs. He pointed to a 2002 study that found that patients treated with Risperdal had a lower risk of relapse than those treated with Haldol. He also noted that the National Institute for Clinical Excellence, part of the National Health Service of the British government, recommends the new drugs as a first-choice treatment for schizophrenia.

Other companies say it is important that they help educate doctors about the intricacies of their drugs. "There is no one who knows more about our products than we do," said Mariann Caprino, a spokeswoman for Pfizer. The company, like many others, gives financial grants for educational events but says that it is not involved in writing the instruction materials.

Industry financing of the Texas guidelines began in 1996, when Janssen agreed to help pay for a survey of dozens of experts about the best way to treat schizophrenia, according to the article by Dr. Weiden and Dr. Dixon.

Texas officials relied on the experts' conclusions to help them write the guidelines, which were first applied to patients in 1997. The initial ones called for doctors to use either Risperdal or one of the earlier generation of antipsychotics. Three years later, Janssen and five other companies helped underwrite an update of the consensus; Texas, in turn, used it in updating the guidelines. The 1999 version established a preference for the new drugs.

Dr. Shon said 11 drug companies had given Texas a total of $285,000 for the project. The effort produced guidelines for treating schizophrenia as well as for treating bipolar disorder and major depressive disorder in adults, and attention deficit hyperactivity disorder and major depression in children.

In all, Texas has spent about $6 million on the guidelines and on educating doctors about how to use them, Dr. Shon said. In addition to the drug industry support, the state has received help from the federal government, universities and nonprofit foundations. The largest grant, $2.4 million, came from the Robert Wood Johnson Foundation, a leading backer of health care research, which was established by the estate of a longtime chief executive of Johnson & Johnson.

David J. Morse, a vice president of the foundation, said that it made the grant because one of its goals is to help find the best possible medical treatments. The foundation has about 50 percent of its financial assets invested in Johnson & Johnson stock, he said, and has former company executives on its board. But it is "completely independent" of Johnson & Johnson, Mr. Morse said.

IN May 2002, a manager in Pennsylvania's public health department reported to state investigators that mental health officials had created a bank account to collect grants from drug companies.

Mr. Jones said the inspector general's office soon dispatched him to look into the report. Pennsylvania's ethics law covering state workers bars them from accepting honorariums and gifts if they are made to influence officials' decisions; ethics officials say the ban can also extend to accepting reimbursements for travel in some cases. Violators can be punished by fines and criminal penalties.

Mr. Jones said he began to believe that drug companies were trying to buy the loyalty of state officials. "The more research I did, the more alarmed I became," he said in an interview.

As he reconstructed the flow of deposits into the account, he interviewed drug company executives and state officials.
Pennsylvania mental health officials, he determined, were beginning to express interest in the Texas guidelines by October 2000. Janssen paid twice for Dr. Shon to fly to Pennsylvania, according to notes from an interview Mr. Jones conducted with Janssen executives in September 2002. Janssen made the grant covering Dr. Shon's travel expenses "to expand atypical usage," according to a company document that was given to Mr. Jones.

On April 17, 2002, Janssen paid for an educational seminar on the guidelines for doctors and nurses working in Pennsylvania's prisons. Each of the speakers - including Steven J. Fiorello, the top pharmacist in Pennsylvania's mental health office, and Dr. Frederick R. Maue, clinical services director of the state's Department of Corrections - was paid $2,000, according to Mr. Jones's interviews and documents he obtained. Comprehensive NeuroScience, a marketing company in White Plains working for Janssen, provided Mr. Fiorello with slides to use as a model for his talk, according to an e-mail message that Comprehensive NeuroScience sent to Mr. Fiorello. In the message, Comprehensive NeuroScience asked him to personalize the slides and then send them back for Janssen's review.

Sandra Forquer, vice president for educational services at Comprehensive NeuroScience, said in an interview that Mr. Fiorello had written his own speech. She also said that Mr. Fiorello had requested that his $2,000 payment be given to charity, but that her company sent it to him directly by mistake. According to Mr. Jones's interview notes, Mr. Fiorello described several instances in which drug companies gave him honorariums but said he was unsure about which ones he had kept and which ones he had given to charity.

Stephanie Suran, a spokeswoman for the Department of Public Welfare in Pennsylvania, said Mr. Fiorello was not available for comment. She said that she could not comment on Mr. Jones's findings because of a continuing investigation.

Mr. Jones's interview notes show that Ms. Forquer also told him that Janssen, through Comprehensive NeuroScience, paid Dr. Maue $2,000 for each of two other speeches, in Orlando, Fla., and Sacramento. A spokeswoman for Dr. Maue said that he had turned over any honorariums he received to the state; state officials confirmed that he had sent the money to the state's general fund.

But Mr. Jones learned that Janssen nurtured other ties to state officials. It named Dr. Steven J. Karp, medical director of Pennsylvania's mental health office, to the advisory board of a newsletter, Mental Health Issues Today, that a marketing firm created for Janssen. Janssen paid to fly Dr. Karp, as well as top officials from other states, to advisory board meetings in Seattle, Washington, D.C., and Tampa, Fla.

ACCORDING to Mr. Jones's interview notes, Dr. Karp said he eventually became uncomfortable about attending the meetings because a Janssen executive was always present. Ms. Suran, the spokeswoman for the Department of Public Welfare, said that Dr. Karp was not available for comment.

The records that Mr. Jones compiled in his investigation are now part of a lawsuit he filed against his supervisors in the Pennsylvania inspector general's office after they removed him from the inquiry. Mr. Jones said he did not know if the inspector general's office had investigated the matter further.

Mr. Jones contends in the lawsuit, which has been transferred to the United States District Court in Scranton, Pa., that his bosses violated his rights by trying to hide the evidence he found.

"I was told that drug companies write checks to politicians on both sides of the aisle," said Mr. Jones, who still works as an investigator in the inspector general's office.

W. Scott Foster, a spokesman for the inspector general's office, said that the office did not comment on lawsuits or its investigations. In court, lawyers for the state health officials have argued that the officials did nothing wrong and did not violate the rights of Mr. Jones.

Pennsylvania officials believe that the schizophrenia guidelines, adopted by the state in 2001, are saving money, Ms. Suran said. In the past, many doctors prescribed more than one drug for schizophrenia patients, the mental health office found. The guidelines, however, rarely allow multiple prescriptions. Preliminary data also show that the mental health of some patients has improved, Ms. Suran said.

Before he was pulled off the investigation, Mr. Jones said, he learned that Janssen was not the only drug company that had made payments to Pennsylvania officials involved in adopting the guidelines. According to Mr. Jones's interview notes, Mr. Fiorello said that Pfizer had paid twice for him to travel to its Manhattan headquarters from Harrisburg for meetings of "an elite group of pharmacists," put him up at one of the Millennium hotels in Manhattan and paid him an honorarium of less than $1,300 for each meeting.

According to the notes, Mr. Fiorello also told Mr. Jones that Pfizer had paid for him to travel with a Pfizer sales representative to Maryland to meet with a mental health official from that state and discuss Pennsylvania's use of the guidelines. Pfizer paid him an honorarium, he said, but he could not remember how much.

Ms. Caprino, the Pfizer spokeswoman, said the company finances development of treatment guidelines to ensure that patients get the best possible medications. The company, she said, plays no role in writing the guidelines. In addition, Ms. Caprino said, Pfizer often hires medical professionals as consultants and pays them for their time.

Pfizer cooperated with Pennsylvania officials as they investigated the payments, she said, and the officials later told the company that it had not acted inappropriately.

SOME payments went to patient groups instead of directly to state officials. In 2002, Janssen gave the Olympia, Wash., chapter of the National Alliance for the Mentally Ill a grant of $15,000 to fly Dr. Shon and other Texans to speak to Washington state legislators about the guidelines, according to Bill Pilkey, the chapter's former treasurer. Each speaker, he said, was paid $1,500.

Dr. Shon said that he gave the $1,500 to the Texas mental health department. In all, he said, he has traveled to more than a dozen states to talk about the guidelines, with most of the trips paid for by grants from either the Robert Wood Johnson Foundation or the federal government.

When he asked the drug industry to cover various expenses, Dr. Shon said, it was because of a lack of state money. "It was the only source of funding to complete or do all the things we wanted to do," he said.

Dr. Shon said he was working with three more states -Alabama, Hawaii and Wyoming - to help them adopt the guidelines.

Referring to the effort to draw up state guidelines that began in 1995, he said, "None of us ever imagined it would grow into what it has become.''

By: FoxChase1803
01 Feb 2004, 03:09 PM EST
Msg. 137338 of 137402
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Biotechs face acid test

By Eli Greenblat

IT WAS a year of buoyant capital markets and insatiable demand from investors, and Australia's listed biotechs took full advantage of both to raise more than $300 million in 2003.

But as the dust settles in 2004, shareholders will be expecting results. And increasingly they will be demanding the kind of results that not only put a rocket under share prices but also buttress balance sheets and deliver profits.

In 2003, profits were scarce. Of 57 listed pharmaceutical and biotechs, only six companies, or 10 per cent, recorded a profit in 2002-03, while only half of those paid a dividend.

Biotechs in the black were market heavyweight CSL, Amrad, Arrow Pharmaceuticals, Australian Pharmaceutical Industries, Institute of Drug Technology and Sirtex Medical. Of those, only Australian Pharmaceutical, CSL and Institute of Drug Technology paid a dividend.

Expect more rowdy annual meetings this year if the rest of the biotech pack, and especially a cluster of middle-ranked players, again fail to deliver, as directors and managers come under the pump from angry shareholders who see nothing but red ink in the accounts and well-heeled executives sitting in plush city offices.

Harry Karelis, managing director of listed investment fund Biotech Capital, said middle-ranked biotechs such as Peptech, Ventracor, Novogen and Chemeq would need to step up to the next level in 2004 and prove they could be the next CSL or ResMed.

"These are all companies that are generating revenue now, or soon should be, and if they don't by 2004 the market will punish them," he said.

Investor patience could be stretched if among the conga line of new floats next year there was very little in terms of quality.

"So long as people are making money in speculative biotech plays they will continue to reinvest, but I'm concerned that there has been some very average floats in the biotech sector towards the end of 2003," he said.

"They have been rushed to the market. I think they have been overvalued and they have raised a lot of money, and I don't think the promoters realise how the markets work."

Mr Karelis, who manages $25 million invested across eight biotech companies, said an important theme for investors this year would be biotechs hitting their clinical milestones.

"Investors need to watch this closely, the milestones, and ask themselves 'is this a great business?' as opposed to 'is this just a great technology?'," he said.

"The daytraders will just be looking for the constant stream of news to push the share price higher, while the institutional investors are going to want meaningful announcements."

Some analysts and chief executives have adopted a bullish outlook and dubbed 2004 the "year of the deal", as giant US pharmaceutical companies desperate for new drugs tap into the growing pool of intellectual property gushing out of biotechs.

Vital Capital chairman Andrew Vizard is targeting an increase in deal-making for his company's investee business, with its Vital Health Sciences subsidiary recently stitching up supply deals for its vitamin E compound.

"After a few years of subdued consolidation, we believe the biotech sector has the potential to really take off in 2004," he said.

Scott Power, senior analyst with ABN AMRO Morgans, said biotechs that completed successful clinical trials this year could find themselves showered with juicy partnership deals from the large overseas pharmaceuticals.

"What we are looking for are good clinical results coming out from around the world, and especially Australia, and with the large pharmaceutical companies' pipelines starting to dry up a little there is an increasing tendency for them to license in development work," he said.

These big multinationals were also suffering from shrinking drug portfolios as the patent protection on certain technologies began to expire.

This would add extra urgency to sealing partnership and licensing deals.

"There's about 700 deals struck each year around these large pharmaceuticals, and what we will see is probably that number increase in 2004," he said.

Biota chief executive Peter Molloy said that if Australian biotechs wanted to clinch similar partnerships or licensing deals with US pharmaceuticals in 2004 they would need to ramp up their investment in research and development, as well as shifting management to the US.

"Fundamentally, this is an industry driven by R&D (research and development) spend; in order to create something of value that you can create a substantial deal around, you need to invest in R&D," Mr Molloy said.

Where Australian biotechs failed was in spending too little on this critical area.

"Our biotechs tend to invest very thinly in R&D, and whereas the average company spend in the US is $US70 million ($92 million) a year, the average in Australia is less than $1 million," he said.

"With that kind of spend it's very hard to create the kind of value that is going to get the attention and deals from big pharmaceutical companies."

But don't expect all deals in the sector to be from traditional sources, says Genetic Technologies chairman Mervyn Jacobson.

"I think that not only will large international pharmaceutical companies and some of the large agricultural companies be interested in doing deals, but also some of the well-known industrial multinationals are starting to identify the huge potential that biotechs offer in focusing on well selected programs," he said.

Dr Jacobson pointed to US giant GE's recent $US9.5 billion acquisition of British life sciences company Amersham as a perfect example of the kind of industrial-biotech marriages that could become popular.

"General Electric's decision to buy Amersham was a very significant move and sends the signal that companies that built themselves up on inventing and selling the electric light bulb or computer components now see biotech as the place to be as it offers benefits for human health and improved quality of life," he said.


By: deathblossom00
01 Feb 2004, 03:51 PM EST
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01 Feb 2004, 03:51 PM EST
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01 Feb 2004, 03:52 PM EST
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01 Feb 2004, 03:53 PM EST
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01 Feb 2004, 03:54 PM EST
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01 Feb 2004, 03:54 PM EST
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01 Feb 2004, 03:55 PM EST
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By: rarboston
01 Feb 2004, 04:00 PM EST
Msg. 137350 of 137402
(This msg. is a reply to 137340 by FoxChase1803.)
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Reticulose: Some promise, too much hype

Bay Area Reporter - September 28, 2000
Jeff Getty, Survive AIDS Writers Pool

Recently, people with HIV have noticed a fairly continuous stream of hype coming from a company called Advanced Viral Research Corporation about its HIV/AIDS drug, Reticulose or "Product-R." Advanced Viral Research Corporation claims that the drug, a peptide-nucleic acid and subcutaneous injectable, may help fight HIV, papilloma virus, and now adenovirus. It also is supposed to help diminish the side effects related to anti-viral medications.
There is only limited data to support these claims; a small placebo-controlled study in Barbados in 1997 that followed 43 HIV patients with 21 receiving the drug for a total of 120 days. Overall the results were less than stellar with the active drug arm showing modest T-cell increases and a .5 log viral load reduction. Also the study showed significant weight gain (the placebo group actually lost weight) and other markers improving such as hemoglobin levels. None of the patients in this study were taking any other AIDS drugs. Since the first study was reported, there have been other reports (unpublished and published) indicating that the drug decreased human papilloma outbreaks and had strong anti-viral effects on adenovirus (causes pinkeye) in the test tube.

So why the hype? Reticulose has been around Since World War II and failed to gain FDA approval in 1962 for influenza. Previous owners of the drug have gone broke and the latest owners, Advanced Viral Research Corporation, which employs Shalom Z. Hirschman, purchased the drug at a fire sale. Hirschman, who was working at Mt. Sinai Hospital in New York as chief of infectious disease, became interested in the drug when a relative with HIV came to him and asked him about it. Hirschman looked into the drug and saw some interesting results in his early work. "I was a doubter like everyone else. When I saw what we were dealing with, my instincts told me that we were opening a new world of medical treatments that are non-toxic," Hirschman said. He went on to join Advanced Viral Research Corporation.

Now Advanced Viral Research Corporation and Hirschman (along with a very aggressive public relations consultant) have set out to raise venture capital so that they can either sell the drug to a larger company or complete drug trials and a full application to the FDA as an HIV anti-viral or immune stimulator. (They are not sure which yet.)

"It's a drug looking for a disease, it has been around forever and every few years it reappears and claims to fight HIV," said Project Inform's Martin Delaney. Delaney does not believe that the drug has any proven merit in HIV disease.

To prove the drug really can help, and to silence its critics, a group of Advanced Viral Research Corporation investors began giving away free supplies of the drug to various patients who called the company after seeing the numerous press releases. The expensive drug, which is produced offshore, is imported for each person individually under U.S. personal drug importation law. The company has been following these patients to see what happens to their lab numbers as well as their clinical health. Seven people have received the drug so far, with all seven wishing to remain on the drug. To date the results have been promising, but the numbers are still too few.

One patient who received the free drug about four months ago is a New York resident, Octavio Perez. Perez had severe AIDS complications in 1992 which left him blind and suffering from wasting. He started his latest HAART therapy about one year ago which consisted of d4T, a protease inhibitor, and abacavir. His T-cell count went up a bit but stayed in the low 200s and his viral load fell but then rebounded to over 100k after a year's therapy. At baseline Perez's T-cells were 232 and his HIV viral load was 580,000 copies. After four months of Reticulose his T-cells were 580 and viral load at 35,000 copies. He also claims that his appetite improved and he gained 12 pounds. Perez also said that his hematocrit (bone marrow output) and liver counts became normal again. "I'm always hungry now," said Perez.

Another patient who received drug three months ago had similar results. Both patients noticed improvements in neuropathy and other side effects from HIV drugs.

I began investigating the drug and the company. I, too, was offered a free supply, and since the drug had no known toxicities, I tried it as well.

Over several months, my T-cells did not go up, nor did I see a sustained viral load reduction. I did notice that my appetite increased dramatically such that I no longer needed to use appetite stimulants or anabolic steroids to keep my weight on. When I stopped the drug (I did so twice because my supply was interrupted) my anorexia returned after about three days. I am convinced that this drug makes me eat. I have noticed no side effects, but long-term effects remain to be seen.

There have been other patients over the years who Hirschman claims saw tremendous benefit, and there have been others who went on to die from AIDS. Hirschman thinks the drug works by adding increased mutation pressure to the HIV virus. He is not sure what effect it is having on the immune system but speculated that it might have strong cellular responses.

Is this another cure looking for a disease? It's makers claim that Reticulose fights papilloma, HIV, and adenovirus (and yes it's said to remove warts as well) Or could there be something hiding here beneath all the hype? Only time will tell, if Advanced Viral Research Corporation can raise the money needed to mount a large FDA clinical trail, we will likely find out more relevant data about the mysterious Product-R. In the meantime, individuals who are able to get the drug for free will likely continue on with Reticulose as long as their supplies lasts.

By: kevtod
01 Feb 2004, 06:36 PM EST
Msg. 137374 of 137402
(This msg. is a reply to 137370 by FoxChase1803.)
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Pull your head out once in a while....

....U might get it......WOOHOO, Great dd, db.....

"In February Project Inform published two separate information sheets about proposed AIDS treatments, one on Reticulose, the other on oxidation therapies (such as ozone and hydrogen peroxide). Both concluded that the treatments are not useful. Anyone considering using them should first obtain the Project Inform writeups, since otherwise it is hard to find any information except from the promoters".

What a joke you are.....