Effective Treatment for MRSA? FDA and WHO Search for New Drug. The widespread misuse of antibiotics has triggered the evolution and spread of lethal multi-drug resistant bacteria — ‘superbugs’ — that are difficult to treat and have few remedies.
Today, antibiotic-resistant infections comprise a looming public health crisis, warns the World Health Organization in a long report on this global threat, released on March 8.
The threat comes from new drug-resistant strains of MRSA — Methicillin-resistant Staphylococcus aureus — and C-difficile that have been spreading in the United States hospitals, and from common infections in developing countries, like tuberculosis.
Each year in the U.S., MRSA alone kills about 19,000 Americans and hospital-acquired infections — most of which are caused by these ‘superbugs’– cause about 99,000 deaths.
If new drugs aren’t developed and antibiotic resistance isn’t solved soon, the world can be brought back to the time before major antibiotics were developed, WHO warns in its report. People will begin to die from common infections as they did before these drugs were created. The medical interventions we take for granted — surgery, organ transplantation, care for premature infants and chemotherapy — will become impossible.
Meanwhile, because of scientific, regulatory and economic hurdles, there aren’t enough new antibiotics in the pipeline to fight the new drug-resistant bacteria.
Antibiotic research and development in the U.S. is slow and prohibitively expensive: On one hand, antibiotics are used only for one or two weeks at a time and these are relatively inexpensive. On the other hand, to ensure the adequate safety and efficacy of all medications, the Food and Drug Administration requires two large and expensive clinical trials for every new drug approval.
In the last 20 years, most drug makers spurned what had become an unprofitable area of research, so today, few medicines to treat the drug-resistant infections have been developed. Right now, only two large companies — GlaxoSmithKline Plc and AstraZeneca Plc — have large antibiotic R&D programs, compared with nearly 20 in 1990.
This is why the Infectious Disease Society of America (IDSA) is pushing for the creation of a new approval pathway for antimicrobials.
At least seven pharmaceutical companies will be able to bring important new antibiotics to market — including a vital drug for a particular pneumonia type — if a new “limited use” pathway is approved, Robert Guidos, IDSA’s vice president of public policy and government relations told MedPage Today.
The proposed pathway is a streamlined process that will give drug companies the incentive they need to develop drugs for the current crop of drug-resistant infections.
Under the SPLMU proposal — called the “Special Population Limited Medical Use” (SPLMU) mechanism — drug makers that want to develop new antibiotics for resistant strains can enroll fewer patients in clinical trials and expect a faster response from the FDA. But they would have to target their antibiotics at specific strains of infections that have few treatment options — including the current drug-resistant bacterial infections.
Overall, the proposed approach “streamlines the approval pathway and enables pharmaceutical companies to study drugs more rapidly and at significantly less cost, the IDSA says in a statement. “It’s a game-changer,” Dr. Guidos claims.
Presented at House hearing
The IDSA presented this SPLMU proposal to the U.S. House Energy and Commerce Health Subcommittee on March 8, during a hearing on the reauthorization of the FDA’s Prescription Drug User Fee Act (PDUFA).
The bill, considered one of this year’s few must-pass bills in Congress this year, will authorize charging fees to drug makers to help cover the costs of reviewing drug license applications. These fees must be renewed every five years, and the current bill expires in September.
Since the fees provide almost half the FDA’s funding, the bill also often becomes a vehicle for broader FDA-related changes.
IDSA is proposing the SPLMU as an addition to pending legislation called the Generating Antibiotic Incentives Now (GAIN) Act, which lawmakers are thinking of incorporating into the user-fee bill.
“Antimicrobial resistance is unequivocally one of the world’s greatest public health threats, and we’ve been sounding the alarm about it — and the lack of new antibiotics in development — for years,” says Dr. Brad Spellberg, IDSA’s Antimicrobial Availability Task Force co-chair in a news release. “This mechanism provides the opportunity to address this public health crisis while there’s still time to fix it.”
It’s difficult to specify which pathogens that would be targeted by drugs reviewed under the proposed SPLMU since each pathogen may have easily treatable, as well as harder-to-treat, strains, says Dr. Spellberg. But acinetobacter, pseudomonas and klebsiella are some bacteria that drugs approved through this mechanism would treat, he explains.
Like the orphan drug system
Thirty years ago, too few companies were investing in drugs to treat uncommon diseases — those affecting fewer than 200,000 Americans. This prodded the U.S. Congress to pass the Orphan Drug Act in 1983.
The law granted companies tax credits, marketing rights and other incentives that helped bring 135 “orphan drugs” to market, according to the National Organization for Rare Disorders.
By allowing the FDA to review certain kinds of antibiotics in the way that it reviews “orphan” drugs for rare diseases, the IDSA-proposed mechanism will make it easier for companies to gain FDA approval for the drugs they develop.
Unlike the Orphan Drug Pathway that targets drugs to treat rare diseases, the new SPLMU pathway targets common diseases like pneumonia and obesity and it wouldn’t be limited to just antibiotics.
This might work to correct today’s situation, where there’s falling investment even in the face of a growing unmet need for antibiotics.
Fighting overuse, off-label prescribing
So far, the FDA has been amenable to the proposal. While admitting that the incidence of drug-resistant bacteria has reached “crisis proportions” in the U.S., the FDA says it only wants to make sure the new antibiotics could be overused — leading again to the development of new drug-resistant pathogens.
The SPLMU pathway itself helps guard against renewed drug resistance: it’s meant for drugs intended for a limited and specific subset of patients. Limiting use this way is meant to help slow the emergence of resistance, the IDSA says.
But the new system could be jeopardized by a common practice of doctors called off-label prescribing: While the FDA always approves drugs to be marketed for specific indications, doctors often prescribe these same drugs for non-approved purposes.
Such off labeling needs to be addressed if the proposed SPLMU pathway for new antibiotics for drug-resistant infections is to be successful, FDA says.
Janet Woodcock, FDA’s drugs center chief says her agency was exploring the possibility of releasing the new drugs under a new label that clearly states that these have “limited approval” and were only tested in a small number of patients. By doing this, the FDA aims to encourage doctors, payers, drug formularies, and patients alike to take the drugs strictly in the way they were approved.
Woodcock admits that the FDA has no real power to regulate medical practice, but she feels that this special labeling would give doctors enough information to use medicine appropriately.
Rather than a regulation with real teeth, the new potential pathway will be more of a “societal contract,” she explains.
“Doctors won’t get in trouble with the FDA, but their malpractice lawyers might not think too highly (of doctors prescribing a limited use drug to a wider population),” she says.
Meanwhile, even with a narrow approval already in force, a drug company will be performing a larger study for approval in a wider population, Woodcock said.
Because drugs approved through the limited-use pathway would also likely be expensive, this would limit their use in the general population, IDSA’s Dr. Guidos adds.
IDSA also vowed to help make sure that any antibiotics approved through the pathway would go to the right patients by working with insurers and doctors. The group can do this because it represents about 10,000 physicians and scientists that focus on infectious diseases.
In its new report on antibiotic-resistant infections, the WHO discussed the five areas it recognized in its 2001 strategy as crucial for controlling antibiotic resistance:
• rational use in humans
• rational use in animals
• infection prevention and control
WHO says the use of antimicrobials in food animals, “is probably a major contributor to the overall problem of emerging antimicrobial resistance.” It also devoted an entire chapter to discussing the need for political commitment to battle AMR.
Data on local resistance patterns could help providers choose the best treatment for patients, but many healthcare facilities have no data on local resistance patterns, the WHO also says in its report. “The lack of adequate surveillance in many parts of the world leaves large gaps in existing knowledge of the distribution and extent of AMR.”
Effective Treatment for MRSA? FDA and WHO Search for New Drug. Posted 15 March 2012. Last updated on 15 March 2012.