Dr. Meg Oeller

Photo by Douglass Oeller

As director of the Office of Minor Use and Minor Species Animal Drug Development, a position she's held since 2008, Dr. Meg Oeller supervises a staff of eight. She retires this week after 30 years with the U.S. Food and Drug Administration.

When it comes to making veterinary drugs, only seven species get much attention: dogs, cats, horses, cattle, pigs, chickens and turkeys. The rest are not economically valued or beloved enough to be moneymakers for pharmaceutical companies.

Moreover, health conditions in even the more appreciated species don't draw drugmakers' attention if the condition is uncommon, affecting a small number.

Enter the Office of Minor Use and Minor Species at the U.S. Food and Drug Administration's Center for Veterinary Medicine. Established by a 2004 law, the office exists to encourage drugmakers to invest in minor species, which include fish, birds, exotic pets and zoo animals; and in diseases that affect small numbers of the major species.

The encouragement comes in the form of fee waivers worth hundreds of thousands of dollars, grants, a chance to sell drug products earlier in the research process, and marketing rights that limit competition for seven years.

As the program's long-time director, Dr. Meg Oeller, describes it, alluding to the Biblical story of Noah, the object is to give consideration to "the whole ark."

Since its inception nearly 20 years ago, the "MUMS" program has resulted in 164 designations, which are projects deemed eligible to apply for grants and receive exclusive marketing rights.

Of those, 31, or just under 20%, have resulted in approved or conditionally approved drug indications. (See more about the difference between drugs and drug indications, and the difference between approval types, below.) Fifty-one projects are in the pipeline. Half of the designations have been shelved or dropped.

Oeller, 69, retires this week after 30 years with the FDA. The VIN News Service sat down with her recently over Zoom to talk about the program's origins, how it works, its successes, disappointments and ultimate goals.

How it began

The MUMS program history intertwines with Oeller's.

A graduate of the Virginia-Maryland Regional College of Veterinary Medicine and a former equine practitioner, she joined the agency in 1993. Oeller had applied for a job reviewing drugs for horses, only to be told at the start of the interview that the opening had been canceled that morning. The embarrassed interviewers went ahead and interviewed her anyway.

Shortly after, FDA hired her to work on aquaculture drugs, "which, as a horse doctor, I was eminently qualified for," Oeller remarked wryly. But learning about farmed fish was useful, especially when her career turned to all minor species — it so happens that two out of three drug uses developed through the MUMS program apply to fish.

In the 1990s, MUMS didn't exist at the FDA. Drug development for minor species was pursued primarily by the U.S. Department of Agriculture. In a program dating to 1982, the USDA funded research at select land-grant universities toward developing products for use in minor-species farm animals (think goats, sheep, pheasants and the like). Once the university researchers completed the studies needed for FDA approval, drugmakers would step in.

"In the majority of cases, the drugmakers were already manufacturing the drugs for use in major species," noted Oeller, who in 1995 became FDA's liaison to the USDA program. "They used their approved manufacturing information along with the safety and effectiveness information generated by the [USDA program] ... to get a very low-cost approval."

As liaison, Oeller watched the USDA program struggle from scarce financial support. "One year, they got a million dollars. Most years, it got half a million dollars," she recalled. In 40 years, the program has resulted in 29 drug approvals.

"It sounds terrible," she acknowledged." But, Oeller noted, citing 2015 data from the Animal Health Institute, FDA approval for a major pharmaceutical company takes 6½ years and $22.5 million for a companion animal drug, and 8½ years and $30.5 million for a food animal drug. The USDA program, she said, "doesn't look that bad, given the funding they got."

The Minor Use and Minor Species Health Act of 2004 reflected a recognition that something more was needed. Oeller said its purpose was to motivate drugmakers to pursue drugs for minor species or minor uses. The FDA was tasked to get it done.

How it works

The MUMS law, in tandem with legislation passed one year earlier, the Animal Drug User Fee Act of 2003, authorized four forms of incentives:

• User-fee waivers. User fees are assessed on drugmakers. Currently, the one-time application fee for a new drug is more than $659,000. A fee of $330,000 applies to a new indication on an existing drug (such as adding sheep to a cattle drug). The sponsor fee runs $150,000. Product and facility fees, assessed when a drug is approved, are about $11,000 and $167,000, respectively. (A separate schedule of fees applies to generic drugs.)
  
  
• Grants. The FDA has given $6.6 million in MUMS awards since 2008. A typical grant is $250,000, potentially renewable for complicated studies, for a total of $500,000 over two years. To be eligible for grants, projects must be disclosed publicly on a designations list.
  
  
• Conditional approval. While drug sponsors pursuing minor use or minor species indications must clear the same hurdles as other drug sponsors in assessing safety, including environmental impacts, they get a break when it comes to product efficacy. Oeller explained that conditional approval is available to drugs for which a "reasonable expectation" of effectiveness is demonstrated, versus "substantial evidence from adequate and well-controlled studies."
  
  For example, she said, a pilot study in 20 dogs with the hoped-for outcome could be sufficient to demonstrate a reasonable expectation that the product will work.
  
  Conditional approval allows drugmakers to advertise and start selling their drug while continuing the studies needed to demonstrate substantial evidence of effectiveness. MUMS drugs may be conditionally approved for up to five years, by which time the drug sponsor must have completed the research needed to achieve full approval. (A similarly named category called expanded conditional approval, created in 2018, is not part of MUMS.) 
  
  
• Marketing exclusivity. Drugmakers who make it to approval get to own the market for that drug for seven years. The FDA will not approve another application in the same dosage form for the same drug indication until after that.

Back to the designations list, which currently has 164 entries: It does not reflect all projects pursued under the auspices of MUMS. Because the designations list is public, Oeller said, some pharmaceutical companies choose to forgo a chance at a grant, instead keeping their projects confidential until they're approved. Those drug sponsors are still eligible for fee waivers and market exclusivity.

As in the USDA program, not every pursuit involves a novel drug. Many sponsors aim to expand applications of already approved drugs to more conditions or other species. For example, one approval entailed adding ferrets to the labeled use of the antiparasitic product Advantage Multi for Cats.

Calculating 'small numbers' in major species

Defining veterinary "minor species" is simple: It's anything that isn't one of the seven major species. But how are "minor uses in major species" defined? No equivalent of the U.S. Centers for Disease Control and Prevention or National Center for Health Statistics exists for nonhuman animals. How does the FDA know what health conditions affect a small number of patients?

Coming up with those numbers was "the hardest thing we did, by far," Oeller said.

Here is what they did:

For the four species raised for food — cattle, pigs, turkeys and chickens — the FDA decided to use sheep, a minor species, as a benchmark. It calculated the collective weight, or biomass, of sheep in this country. Then it said: How many cattle equal the collective weight of sheep? That's how many cattle would qualify as a minor number. The same math was done for pigs, turkeys and chickens.

Figuring the companion animal numbers is more complicated. It's an economic calculation that takes into account the population of the species (based on an American Veterinary Medical Association census), the cost to a company to get a drug approved, and how long it takes for the company to recoup its investment.

This month, owing in part to a population increase in dogs and cats, their minor-use qualifying numbers went up, from 70,000 to 80,000 in dogs, and from 120,000 to 150,000 in cats.

Drug 'indexing'

There's one more way under the MUMS law that drugmakers can hasten to market products serving minor species that aren't raised for food. It applies to, for example, zoo animals, laboratory animals, birds, ornamental fish and exotic pets like small mammals and reptiles. The process, in place since late 2008, is known as drug indexing.

With indexing, the FDA is much more relaxed about the data it requires to allow products to be sold. To demonstrate safety and efficacy, drugmaker applicants (called "requestors" rather than "sponsors" under this process) can cite non-peer-reviewed as well as peer-reviewed studies — "stuff they'd never accept" for drugs being considered for approval, Oeller said.

The requestor does have to commit to using good manufacturing practices, show that the product won't harm the environment and provide information on safety to the human user and the target animal, or patient.

Indexed drugs cannot be used for anything but the labeled use (most approved drugs can be used off-label, also known as extralabel use), and if problems develop, the FDA can remove them from the index fairly readily, Oeller said, making continued sales illegal.

Indexing has ushered 16 drugs to market so far, with more in the pipeline, Oeller said. Examples include pain relief for rats and mice; a topical antiseptic for raptors, pet birds, captive small mammals, captive reptiles and zoo mammals; and an implant to manage adrenal gland disease in domestic ferrets.

Where things stand

Of the 31 designated drugs approved for minor species or minor uses in major species, 22 indications are for fish, four are for dogs, and one each is for goats, sheep, honeybees, ferrets and cattle.

The drugs for dogs, for example, are Tanovea (rabacfosadine succinate) and Laverdia (verdinexor) for lymphoma; Canalevia (crofelemer) for chemotherapy-induced diarrhea; and Vetoryl (trilostane) for Cushing's syndrome.

Many pursuits have fallen by the wayside, usually ended or suspended by the drugmaker. They include a product to masculinize female tilapia early in their life stages; an implant to treat eye disease in horses; and a drug to control certain respiratory infections in pheasants.

Projects can be revived. Oeller explained: "Sometimes they're terminated because the companies lost focus, or there was Covid. Sometimes, they're just having financial issues. There are all kinds of reasons they want to take a break. They can come back [saying], 'Look, we got all this venture capital, or whatever, and we're good to go again.' "

While Oeller said she's unsurprised that the MUMS program has proven most productive for aquaculture, the lack of anything for cats was unexpected. At the same time, she noted: "That's on the [public] designations list. There are probably some in proprietary files ... that we can't disclose."

She acknowledges that the MUMS programs haven't been an unqualified success. "We've taken a big step forward from nothing, but you know, we've been at this for awhile, and I'm about to retire and there will be new leadership in the office — but even if I were staying, it's about time to do a reassessment," she said. "We need to fine-tune what we have and find out what we still need to lead to more approved products for these underserved populations."

One thing she'd do is ask drugmakers today what would lead them to pursue products for minor uses and minor species.

"It's harder than when I started," she mused. "Back in 1993, there were a lot more companies. Many companies have merged. And when they merge, they say, 'Let's take my top 10 drugs and your top 10 drugs and keep those on the market.' They want to develop more blockbuster things, and quite honestly, a drug for ferrets doesn't cut it."

One approach would be to further encourage companies to add indications to existing drug labels, she suggested: "Let's get the sheep and goats on all the cattle labels. Let's get game birds on the turkey labels. ... If it's a chicken drug, let's add the pheasants and the quail and the partridges and the duck. Let's find a way to do that efficiently, and the company doesn't have to do a separate product. They just figure out the accurate dosaging and withdrawal time."

In short, Oeller said: "My goal in a perfect world is that all the things that veterinarians and animal producers need to treat their animals would be legally available and on a label so that they know how to use it properly. That's the dream, and we're a long way from that. But I still have hope."