Antibiotic Trial Without Comparator Would Lower R&D Cost, Wyeth Exec Says

Antibiotic trials without comparator drug arms would lower development costs, Wyeth Antibacterial Research Director Steven Projan, PhD, suggested.

"How about considering doing our Phase III clinical trials without a comparator?" Projan said Sept. 15 at the Interscience Conference on Antimicrobial Agents & Chemotherapy in Chicago.

Projan suggested that companies and FDA should "agree beforehand, based on Phase II data and historic norms, what our target efficacy rate should be and the number of evaluable patients we need."

"It's really a win-win idea, and I challenge the agency and the people in this room to consider how we can do this. It certainly will significantly reduce costs and risks, and really reducing risks is what the industry is after."

Center for Drug Evaluation & Research Lead Medical Officer for Antimicrobial Drug Development & Resistance Initiatives John Powers, MD, responded that certain factors, such as the severity of some conditions, complicate determining a target cure rate.

"The problem is that we need to be pretty clear on what the cure rate actually is," Powers said, adding that the margin of efficacy has to be scientifically based.

"I think this is where the FDA challenge back to industry is going to come....The submission of higher quality data may allow us to do less quantity. It is probably an unreasonable request to expect that we would get less quantity data that is also of less quality. That would not make sense for the public health," Powers said.

Increased use of surrogate endpoints would also simplify the regulatory process, Projan maintained.

"After all, isn't the purpose of an antibiotic to get rid of the bugs?" he said.

Powers said that surrogate endpoints were acceptable as long as they correlated with a clinical benefit.

"In fact there's a whole guidance about using surrogate endpoints, and probably the best example of that is the use of viral load in HIV....A microbiologic endpoint as a surrogate market is possible, but it has to translate into a clinical benefit," Powers said.

"We've actually tried to do some of this work for the companies and have looked at some of this recently," he added.

He noted that FDA plans to publish a letter in the October issue of the Pediatric Infectious Disease Journal detailing a poor correlation between microbiologic endpoints and clinical outcomes in otitis media.

Powers noted that "63% of children who still have a bacterium in their ear at day two are clinically cured. So that makes it very difficult to use some of these microbiologic endpoints in less severe disease."

Projan pointed to Aventis' Ketek (telithromycin) as an example of the escalating costs of antibiotic development and the uncertainty of rapid approval even in the face of massive amounts of data.

"Aventis was asked for more safety data. They ran the largest safety trial in the history of antibacterials, and found pretty good safety...However, [Ketek] is still not on the market now," Projan said.

Aventis received an "approvable" letter for Ketek in June 2001, requesting additional safety data. The company filed safety data from a 24,000-patient trial in 2002 (¹ (Also see "Aventis Ketek Will Return To FDA Advisory Committee Jan. 8" - Pink Sheet, 4 Nov, 2002.), p. 16).

Aventis received a second "approvable" letter Jan. 24 that requested "additional analyses and information" (² 'The Pink Sheet' Feb. 3, 2003, In Brief).

Aventis will respond to FDA's request within a matter of weeks, the company reported at the Bear Stearns Healthcare Conference in New York in September.

Such a lengthy regulatory process can discourage innovation, Projan said.

"I can guarantee that if companies like ours are forced to do 24,000-patient safety studies, then telithromycin will be...the last antibiotic ever developed for community infections," Projan said.

Although the antimicrobial market can be less risky than other sectors because of well-defined models to predict efficacy and experience in safety issues, the number of approvals of antimicrobials has dropped, according to Powers.

The average number of antimicrobials approved each year has fallen from 16 in the 1980s to 8 in the late 1990s. There have been two approvals to date in 2003.

"When you look at the list of best-selling drugs, it doesn't include any antimicrobials....After listening to the first four speakers, you can see why anti-depressants are number one on that list of drugs," Powers joked.

"Obviously the treatment of chronic diseases are more profitable. The longer you stay on a drug, the more money somebody has to spend. And, antimicrobials for the most part are short-term treatments," Powers observed.

"As we've heard a lot from the other speakers, when a new antimicrobial comes out, there is probably a justifiable rule amongst clinicians to reserve that new antimicrobial to prevent...the inevitable development of resistance."

A first-in-class antimicrobial was approved on the eve of the conference. Cubist's Cubicin (daptomycin) for complicated skin and skin structure infections was approved Sept. 12, the second antimicrobial to be approved this year (³ (Also see "Cubist Cubicin Marketing To Highlight Single Daily Dose Of Antibiotic" - Pink Sheet, 22 Sep, 2003.), p. 22).

This was a special case, according to Projan.

"It's very difficult for biotechnology companies to do what Cubist did, to raise the money to run their own clinical trial for daptomycin. And I think that's going to be a rare exception," he said.

New drugs in the area are not selling as well as expected, Projan said, citing the disappointing showings of Aventis' Synercid (quinupristin/ dalfopristin) and Pfizer's Zyvox (linezolid).

The high cost of these drugs is seen as a major barrier to their use (⁴ (Also see "Synercid, Zyvox Drug Pricing Discourages Use, IDSA Rep Says" - Pink Sheet, 11 Mar, 2002.), p. 27).

"I think linezolid is certainly doing better than Synercid, but it has not captured the projected $600 mil. dollar a year market it was originally hoped to," Projan said.

"It isn't really clear to me why companies should invest in antibacterials if we see our costs exploding, if we don't see resistance as the market driver it was supposed to be, the return on investment is unfavorable, [and] it's hard to get resistance indications based on the current observations people have made about the approval process."

"We have a crowded and confused market with dozens, if not hundreds, of effective agents that are available," Projan added.

According to Projan, 10 of the top 15 pharma companies have spun off, curtailed, or eliminated antibacterial drug development since 2000.

Projan suggested that wild card exclusivity would encourage companies to do research in the anti-infectives area.

"That's immediate cash and would have a very large effect on the net present value calculation and would certainly stimulate research in companies in the industry," Projan said.

Wild card exclusivity - an idea that has also been discussed for bioterrorism products - would allow companies a patent extension on the product of their choice in return for R&D on a less commercially attractive indication.

Powers emphasized the limits on FDA in seeking such new exclusivity. "What the FDA cannot do is lobby Congress for some of these economic incentives," Powers said. "We can only operate within the current regulations at the FDA."

Powers pointed to FDA's development of a list of criteria for pathogens "of public health importance" as an action being taken within the agency to encourage antibiotic R&D.

The FDA list would allow for the possibility of resistance claims in labeling and expedited review.

The list's criteria include: the organism is of sufficient prevalence in the population with the disease under study; there are limited available therapies because the organism is multi-drug resistant; and the organism causes serious and severe disease (⁵ (Also see "Pathogen List Development Guided By Limited Therapy Availability – Cmte." - Pink Sheet, 24 Mar, 2003.), p. 43).