Small Clinical Trials Feasible for New Limited-Population Approval Pathway

Researchers and patients seeking new treatments for infectious disease and critical conditions are pressing the Food and Drug Administration to adopt a streamlined development and approval pathway for new antibiotics and other life-saving medicines. The concept, which also was recommended in a September 2012 report from the President’s Council of Advisors on Science and Technology (PCAST) on “propelling innovation in drug discovery, development and evaluation,” was discussed at a February FDA public hearing, as well as at a seminar sponsored by the Pew Charitable Trusts.

The main idea, as outlined in a Limited Population Antibacterial Drug (LPAD) approval mechanism proposed by the Infectious Diseases Society of America (IDSA), is to permit FDA approval of a drug for a very narrow indication based on smaller, faster clinical trials for targeted patient populations. Specific labels would limit prescribing to the designated uses, and approval would require postmarket studies and monitoring.

Jeffrey Spaeder, chief medical and scientific officer at Quintiles, described the LPAD proposal at the FDA meeting as a “feasible pathway that can be operationalized today.” This approach has to incorporate real-world data to identify study sites most likely to have relevant patients and to ensure the accurate powering of pre–registration studies in stratified subpopulations. Such studies should be able to incorporate surrogate endpoints, biomarkers and patient measures that can inform the design of registries and post-approval studies, while observational studies could monitor and evaluate real-world drug use in approved subpopulations. “We must think big, start small and scale up fast,” Spaeder advised, to build an alternative pathway so that “patients can benefit without delay.”

Some researchers and advocates say the new pathway is not necessary, given provisions in last year’s FDA Safety and Innovation Act (FDASIA) that authorized speedier FDA approval for “breakthrough” drugs and added exclusivity for new orphan drugs and antibiotics. FDA officials say they already have considerable authority to approve critical treatments based on streamlined trials and limited evidence. But patient advocates consider the additional incentives provided by LPAD important for developing new treatments for Parkinson’s, leukemia, tuberculosis, transplant patients and various rare conditions, as well as infectious diseases.

To move forward, FDA and sponsors need to address a number of issues, starting with what evidence FDA would require for limited population approvals and whether special labels or “limited use” identifiers would discourage inappropriate prescribing. Pharma companies want LPAD to be voluntary and not imposed by FDA, and there’s strong opposition to a ban on off-label prescribing from both industry and physicians, who want flexibility to prescribe a new drug for say, a brain infection, even without studies for that condition.

The role of payers in spurring development of new antibiotics was examined more closely at the Pew meeting. Even with a less costly testing and development process, the limited markets for these therapies means premium prices – high above those for generic antibiotics. Payers said that they will look for data from sponsors on how well the new treatments prevent deaths, shorten hospital stays or reduce readmissions, along with evidence on the severity of the condition and lack of alternative treatments.

“Antimicrobial stewardship” programs also promise to encourage appropriate prescribing of limited use antibiotics, and monitoring and mining electronic health records and other databases could help track how the drugs are prescribed and their impact. As Paul Huckle, head of regulatory affairs at GlaxoSmithKline, summarized at the FDA meeting, a combination of appropriate FDA labeling, appropriate promotion and education by the sponsor, and underlying stewardship at institutions and by the community should provide “a pretty good way of managing use of these products in the antibiotic space.”