Monday, March 15, 2010

Drug Development: Where are the New Antibiotics?

As resistance to antibiotics continues to develop and spread, the medical community can no longer afford to ignore a distressing reality: the lack of new antibiotics in the development pipeline. Resistance is causing current antibiotics to lose their efficacy, and we are left without viable alternatives. This is largely a result of the regulations and economics of drug development, a process that makes antibiotics undesirable classes of drugs to produce and market.

Drug development is a heavily-regulated, step-by-step process that is meant to ensure that a drug is safe and effective before it appears on the market. Pre-clinical studies in animal subjects or test tubes aim establish the drug’s general safety. Phase 0 trials, a new addition to the regulatory process, involve very low, single doses of the drug given to human subjects to test its effects against what was seen in pre-clinical studies. In Phase I trials, small groups of humans are given escalating doses of the drug to find the proper therapeutic dose and again to check the safety of the product. Phase II involves a larger group of human subjects and is intended to confirm the safety and efficacy of the drug at a pre-determined dosage. Phase III studies are much more extensive, involving randomized, double-blind trials with large human groups; the end-goal of Phase III trials is a regulatory submission. Once the drug is approved, Phase IV trials continue to monitor drug’s effects once it is being marketed and sold.

This exhaustive process often takes eight to ten years from beginning to end and costs, based on multiple estimates, between $800 million and $1.7 billion per drug. Many new drugs get rejected along the way when efficacy expectations are not met or unforeseen side effects arise in trials. Because of the costs and risks associated with this process, the likelihood of a drug getting to market, and the potential profits if it does, are the guiding factors that determine what drugs a company will invest in. A drug’s net present value, or NPV, is risk-adjusted to calculate the attractiveness of a drug in development. And for new antibiotics, the costs and benefits often don’t add up.

Antibiotics cost as much and take as long as other drug classes to develop and test but often bring in less revenue for the companies that produce them. While a patient requiring antibiotic treatment will often only need medication for 1-2 weeks, those on heart, cholesterol, or blood pressure medications will take these drugs for years, if not decades, of their lives. In addition, the burden of antibiotic resistance means that new drugs will inherently become less useful – and therefore less marketable – over time, and that doctors will be pressured not to prescribe the drug unless it is absolutely necessary. And while a broad-spectrum antibiotic that can be used for a range of infections is more profitable for the pharmaceutical company, resistance trends mean that narrow-spectrum drugs are preferred in the clinical community.

Most of the antibiotics in the development pipeline are part of the same drug classes as those that are marketed now – meaning resistance is likely to develop sooner, because the drugs work by similar mechanisms. The Infectious Diseases Society of America reports that since 1998, ten new antibiotics have been approved by the FDA, and only two of those work on novel targets and are thus not at risk for cross-resistance. The lack of new antibiotics is especially a problem for gram-negative bacterial infections, which are more difficult to target than gram-positive bacteria.

Some professionals in the field believe that market conditions are creating renewed interest in antibiotic development, but others argue that regulatory action must be taken to make these classes of drugs more appealing (more profitable) for pharmaceutical companies. For example, the government could approve patent extensions for antibiotics, meaning that pharmaceutical companies could be the sole marketer of these drugs for longer before generics were made available, increasing the window of maximum revenue. Currently, U.S. drug patents have a 20-year duration that begins before the start of clinical trials. But even if regulatory measures are taken, the danger of coming up empty handed for treatment of resistant infections remains. Finding new modes of action and targets for antibiotics remains a challenge, and any new drug still faces a decade-long process of testing and development before it may be approved.

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