You can find my petition linked above or in the FDA docket: http://www.regulations.gov/#!documentDetail;D=FDA-2013-P-0522-0001, or if that does not work, here: http://www.regulations.gov/#!docketDetail;D=FDA-2013-P-0522
In August of 2014, the FDA denied my petition. You can download that PDF or visit the docket: http://www.regulations.gov/#!documentDetail;D=FDA-2013-P-0522-0009
Why did I file this petition and what did the FDA say in response? I submitted the petition because the FDA continues to operate in a biologically bankrupt, factually incomplete, and outdated paradigm in how it assesses the risks of pregnancy drugs. And the consequences of its plodding "Let it become conventional wisdom, and then maybe we'll think about it" regulatory posture has spawned disastrous consequences. To the FDA, fetal germline simply does not exist, and to the extent there might be little critters in those cute little fetal gonads, they are unimportant and unworthy of protection.
Imagine if the FDA told the public, "We will assess dangers of pregnancy drugs, but refuse to consider any effect on the heart. The heart is a difficult organ to study, so we just won't do it!" People would of course be dumbfounded at the flippant stupidity of such an attitude, and the staff would probably be fired in humiliation. But this is exactly what's happening at the FDA with regard to a different organ, the gonads, or at least the precious materials that lie within them.
What did the FDA think about my petition? In response to my fairly non-controversial assertion that endocrine-disrupting and other chemicals can adversely affect mammalian germline, the FDA took the position that it was not their nor the manufacturer's burden to show safety, but rather it was my burden to prove the germline effects of Diclegis, or, presumably, any other drug that may enter a pregnant body. The agency, which doesn't even bother to ask the question about germline effects in its protocols, said that while I had offered support for the general proposition that hormonally active chemicals can impair germline synthesis, I had failed to offer "human or animal data for Diclegis which demonstrate or suggest that Diclegis disrupts the human fetal germ cell epigenome."
My friend, a wise attorney, once offered me an analogy for this type of hyper-narrow regulatory approach. Imagine, she said, a red Ferrari drives down the highway at 100 miles per hour, crashes, and kills four people. Now, imagine that the lawmakers' response was to pass a bill preventing red Ferraris from hurtling down the highway at 100 mph. In this narrow approach, the hazards of other cars, perhaps moving at similar speeds, would be ignored. But this is the FDA's approach. A drug/chemical (by the way, there is no distinction between drugs and the broader category of chemicals except as to marketing and packaging, they are both just man-made molecules with biological effects) must have an exact molecular structure already proven harmful, otherwise it will bypass the artificially constrained regulatory apparatus.
Next, the FDA actually admitted that no studies have yet examined germline or F2 effects of the drug, but was oddly unconcerned about that absence of information: "All of the articles address in utero and postnatal exposure in first generation (F1) offspring with a focus on congenital abnormalities/fetal malformation (for example, limb defects) and other birth defects (for example, clefts of lip and palate). None of the articles provides information on the second generation [F2 (grandchildren)]. DBRUP did not find any articles that demonstrated a risk to the fetal germline associated with the use of doxylamine and pyridoxine, alone or in combination, with resulting neurodevelopmental pathology in F2 offspring."
Okay, let me get this straight. The FDA is basically saying, "We haven't bothered requiring F2 studies, so, um, that's somehow proof of lack of F2 impacts, or proof that F2 studies are not needed!" Okay, thanks FDA, that's very reassuring.
Finally, the FDA in its vast wisdom stated that if no gross anatomical birth defects appear in F1, it sees absolutely no reason to be concerned about potential molecular impacts in the germline (F2). In other words, the agency has taken the position that it's impossible for the germline to be affected if there are no obvious somatic defects. Given that germ cells and somatic cells undergo completely different forms of molecular development and programming, I cannot figure out how the FDA reached that facile and falsely reassuring conclusion. In addition, the FDA is notorious for limiting its examination of somatic impacts to "birth defects" rather than long-term effects, including on neurodevelopment, or on subtle effects including sexual dimorphism of the brain, or personality effects, so its unwavering belief in the non-effects of Diclegis, based on studies that only surmised a portion of potential somatic cell effects, are surely premature.
I also asked that the FDA recategorize Diclegis as a Category C drug instead of Category A, since no research has yet ascertained potential effects on fetal germline. Again, the FDA felt this question was unimportant, and eclipsed by the data showing no significant F1 somatic birth defects: "Given the extent of the human studies done to support the approval ofDiclegis (and Bendectin and Diclectin before that, as well as the clinical evidence that supports the OTC indications for doxylamine) that show no adverse effect on the fetus, we do not believe redesignation of Diclegis as Pregnancy Category C is appropriate."
What does all this mean? Was my first stab at shaking the shoulders of the slumbering FDA a total failure? Should I try, try again? Here's my take on it (always subject to change). In some ways I think my petition was historic—it represented the first time in FDA history that anyone has raised the question about the potential adverse impacts of pregnancy drugs on fetal germline. Second, there is a growing appreciation among regulators and toxicologists concerning germline vulnerability, particularly during the fetal development phase, owing to the fine-tuned and evolutionarily conserved epigenetic reprogramming of the germ cells. So, perhaps in the next stab the general awareness of this phenomenon could make the regulators more open to these questions. And third, at a certain point, this humongous blind spot in how the FDA thinks about drug risk will just become plain obvious enough to everyone outside the FDA, that to save face the agency will need to finally address these questions head-on in the approval and labeling process. And right now, placing the burden on consumers to be PhDs in molecular biology with millions of dollars to fund private toxicological research in order to plead their case about a rather obvious question that should be inherent in the regulatory process, is just, well, pathetic and unconscionable.
I do have a second petition planned, with regards to another popular pregnancy drug, and one with known endocrine-disrupting effects. It will raise urgent questions — questions that should by now be routine, but tragically are not. News on that coming soon. But the fundamental question is this: does the FDA exist, by Congressional mandate, to pro-actively protect human health, even somewhat ahead of the curve of conventional wisdom, or to defend its crusty old bureaucratic machinery stuck in convenient but biologically false bygone paradigms? At this point, it often appears to be the latter.