The declining number of recent approvals is often attributed to unnecessary delays and denials by FDA. For example, various high-profile therapeutics received approvable letters in 2007 and multiple product evaluations were delayed or their applications denied.
Some analysts and company executives believe that controversies over the safety of Vioxx and other pharmaceuticals have stung FDA. As a result, the agency is being overly cautious, defensive, and unassertive. Some have noted that FDA is taking a longer time and/or inducing delays in approvals of new products including those with indications similar to already available drug in addition to stalling or denying supplemental approvals for new indications.
However, relatively few filings for biopharmaceuticals have been arbitrarily denied or without some seemingly valid reason, significantly delayed, or put on long-term hold. There usually has been some obvious problems with the filings, often related to trial protocols and/or products not attaining their preset primary endpoints in pivotal trials.
High-profile examples include FDA refusing to approve Provenge, an immunotherapeutic prostate cancer vaccine from Dendreon, despite a positive recommendation from its own review committee. The agency also refused Genasense, an antisense drug for relapsed or refractory chronic lymphocytic leukemia from Genta.
The decrease in approvals, however, could be linked to the fact that the FDA has subtly shifted, or is adjusting its standards to be stricter or more restrictive in terms of efficacy and safety. Alternatively, it may simply be doing its job more slowly, with inadequate staff and resources taking its toll. Or, it could well be the result of poor decisions and execution by sponsors, including inadequate trials.
The low number of recent biopharmaceutical approvals is probably not due to fewer products in development—pipeline databases and other sources generally show that the number and percentage of biopharmaceuticals vs. other pharmaceuticals have been steadily increasing. Rather, it appears that fewer products are making it through pivotal Phase III trials.
Most biopharmaceutical filings receive priority review. Sections are filed as completed, often with pivotal trial results being the last part to be filed. As a result, related delays and denials are more dramatic compared to the sponsors never filing or FDA refusing to file a full application with completed pivotal trial results.
FDA may well be subtly shifting its approval criteria regarding safety and efficacy, but most of the biopharmaceuticals affected had problems, usually showing insufficient efficacy and safety in pivotal trials. It appears premature to blame FDA for systematically, needlessly, or arbitrarily delaying or denying approval of biopharmaceuticals.
About two dozen filings for biopharmaceuticals are currently pending at FDA and about two dozen more are expected in 2008. Thus, unless the great majority of pending and upcoming applications are rejected, delayed, or abandoned, an increase in approvals can be expected in 2008 and 2009.
If this proves to be the case, FDA approvals of biopharmaceuticals appear to be on a three- to five-year cycle. Thus, we are now probably in or near the end of a trough.
New Biopharmaceutical Entities
In this article, new biopharmaceutical entities (NBEs) are defined as products with active agents that have novel structures or sources and also those with substantially novel formulations. The criteria for determing NBE and novelty status are not the same. A product can be an NBE, be new and unique, but not novel. Of the 11 drugs approved in 2007 and 12 in 2006, 10 in each year were NBEs. These include all but Afluria and FluLaval, which are essentially biogeneric versions of prior influenza vaccines, and Omnitrope, the seventh recombinant somatropin product appproved by FDA.
That NBEs make up such a high percentage of the approved biopharmaceuticals is not surprising. The reverse is true though with small molecule drugs, where a much smaller proportion of original approvals are for novel molecular entities for which multiple routes for generic/abbreviated approval are available.
But NBEs have varying degrees of novelty in terms of active ingredients and indications. Most 2007 approvals were me-too products in which the active agents were similar in many respects to those in prior products and/or approval was received for the same indications as prior products. 2006 approvals were generally more novel in terms of active agents and indications.