REGULATORY GAUGES OF SUCCESS

Filing With the FDA at Top of Canadian Firms’ To-Do Lists

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By Deborah Komlos

Home turf product approvals may give enough cause for celebration, but Canadian drug and biologic firms strive for more.

These companies know that success isn’t just measured locally. They also need validation of their work through the regulatory system to the south. As a result, it’s not uncommon for Canadian firms to initially seek product approval from the U.S. Food and Drug Administration (FDA) — and with good reason.

“Everybody wants to get their drug to the FDA obviously because the U.S. is the biggest market, so globally, everybody goes there,” says Brian Bapty, PhD, biotechnology sector analyst with Raymond James Ltd. (Vancouver, BC).

But breaking into a big market isn’t the only critical measure to consider.

“At the end of the day, the FDA is recognized as pretty much the world standard,” Bapty says.

“They are helping you design trials. They are giving you the parameters by which they’ll approve a product. They’re trying to protect the patient,” Bapty explains. “So, their objective is the ‘do no harm’ objective: to keep the patient safe, provide a facility, provide a structure to enable a drug to move safely through the clinical-development process, and prove an end point, prove a benefit to the patients beyond some categorical risk of deleterious side-effects.”

Naturally, the typical goal is to reach the end of Phase III and then gain product approval. However, reaching that stage is not very common, Bapty says.

The FDA approves anywhere from 15 to 40 drugs per year, “and that’s a pretty wide spread,” Bapty says. “But that’ll tell you that of all the companies working in this space, there are not many drugs that actually get to the FDA in a one-year span — that’s global.” And, those drugs “are not 100-per-cent different from drugs that are out there; they might be next-generation compounds,” he adds.

Monetary Milestones

When approvals do come, the results that follow are well worth the wait for a firm — both financially and strategically.

AnorMED Inc. (Langley, BC) experienced such an outcome this past October when the firm announced the FDA approval for Fosrenol®. In March 2004, AnorMED sold the global patent rights for Fosrenol to Shire Pharmaceuticals Group PLC (Basingstoke, U.K.). Included under the terms of agreement was a payment of $18 million US to AnorMED upon receipt of U.S. approval for Fosrenol, a treatment for high phosphate levels in the blood.

“It’s obviously nice to have this lump sum payment as we’re moving into a Phase III trial,” says Michael J. Abrams, PhD, AnorMED’s president and CEO.

AnorMED had an End of Phase II meeting with the FDA in September 2004, Abrams says, and agreed to file a Special Protocol Assessment (SPA) for its lead drug candidate, AMD3100, a stem cell mobilizing agent for stem cell transplantation in cancer patients.

“This is a process that the FDA has been using quite a bit lately, where we basically agree beforehand on a trial design and end points, and the idea is that if we can then hit those end points, it’s an agreement to approve the drug, and these are binding unless some unforeseen issues come up,” Abrams explains. Such issues could include safety concerns, or even the chance that a disease cure is found, he adds.

AnorMED received word on its SPA in early December for its Phase III program, which comprises two pivotal trials of AMD3100. The company announced it has initiated the trials and hopes to enrol the first patient in early 2005.

Further anticipated payments regarding Fosrenol, Abrams says, are $6 million US pending European Union approvals — it was approved last March in Sweden, channelling $1 million US to AnorMED — and $6 million US upon approval in Japan.

Ambitious Generics

For Bioniche Pharma Group Ltd., FDA approval last November of its Abbreviated New Drug Application (ANDA) for Sotradecol™ Injection — a treatment for sclerotherapy, or non-surgical vein removal — was a long time in the coming, says Albert Beraldo, Bioniche Pharma’s president and CEO, based in Pointe-Claire, Que. Bioniche Pharma is a business unit of the Human Health division of Bioniche Life Sciences Inc. (Belleville, ON), with manufacturing facilities located in Galway, Ireland.

“We’re a small company, and we’ve been working on this one for about three years,” Beraldo says. “We were very pleased to get the approval because we’ve been sort of waiting for a while.”

The ANDA process normally takes between 18 and 24 months, he adds, but in Bioniche’s case the firm had to address some queries on its submitted product dossier, which lengthened the time frame.

“This one was an investment considerably larger than some of the other ANDAs we’ve developed,” Beraldo says. “But again, we believe the payback on this one is better as well and the fact that we were able to trademark the Sotradecol name.” The original product was discontinued years ago, and what Bioniche has done, Beraldo says, is introduce an improved version.

In filing an ANDA, a firm must show that a generic product is “equivalent to either the innovator product that’s still on the market, or other generic competitors that are out there,” Beraldo explains.

He points out that Bioniche’s product preparation route involved a slight diversion from the standard, where a firm finds an active pharmaceutical ingredient (API) supplier from which to source a raw material for a compound. In Bioniche’s case, Beraldo says, there was no commercially available source for the API, so the firm had to work in conjunction with a couple of companies to develop that raw material.

The API — sodium tetradecyl sulfate — that had been used in the marketplace in the past was of a formulation that the firm felt did not meet the pharma industry’s standards “in any way, shape or form and would never be approved by the FDA,” Beraldo says. “We had to develop an active pharmaceutical ingredient that in all ways met the stringent GMP requirements associated with pharmaceutical products.”

Beraldo is quite optimistic about Bioniche’s progress with Sotradecol.

“We were granted an expedited review simply because we were meeting an unmet medical need, being that there was no approved product on the marketplace,” he says.

Although Bioniche’s products “are not necessarily going to be the $100-million-a-year products,” Beraldo says the company is aiming to submit four or five ANDAs per annum. This way, the firm can have a steady incoming product stream. “We will continue to focus on what we would call niche areas — therapeutic classes that are in line with some of the products we have already developed,” he says.

The Approvals Route

While smooth sailing toward market approval for drugs or biologics is the ideal, stumbling blocks can fall along the way. Such was the case experienced by Inex Pharmaceuticals Corp. (Burnaby, BC) early last December.

The firm’s submission for accelerated approval for its lead drug, Marqibo™ — a proprietary treatment for relapsed aggressive non-Hodgkin’s lymphoma — was unanimously voted against by the FDA’s Oncologic Drugs Advisory Committee (ODAC), one of the agency’s several advisory committees that comprise external experts to advise on applications to market new drugs.

Speaking on a conference call after the decision, Inex’s president and CEO David J. Main said that, based on ODAC’s vote, the firm believes the FDA will not grant accelerated approval when it makes its final decision on the firm’s New Drug Application (NDA), expected by January 15, 2005.

“The panel concluded that there was other therapy available for these patients and that the data that we presented was not compelling enough in the context of these other available therapies to warrant accelerated approval,” Main said.

“Certainly, from our analysis in viewing the patient population that we enrolled in the trial, we believe the results that we reviewed today are compelling for that population and that Marqibo did provide an alternative that is not currently available to those patients. But that is not what the panel concluded,” he said.

Main said that future plans for Marqibo will be solidified after considering the FDA’s final decision.

Also awaiting FDA feedback — expected in the first half of 2005 — is Biovail Corp. (Mississauga, ON), which filed four NDAs early last year.

“We believe that is significant considering that over the last 10 years, the average number of NDA applications presented to the FDA is 117,” says Kenneth G. Howling, Biovail’s vice-president, Finance and Corporate Affairs. The pharma firm’s main focus covers the areas of cardiovascular disease, CNS disorders and pain management.

The FDA is relatively predictable in terms of when firms may hear responses on their NDA filings in accordance with defined time points set out under the Prescription Drug User Fee Act, explains Gregory J. Szpunar, PhD, Biovail’s senior vice-president, Research and Development, and CSO, based in Bridgewater, N.J.

“There’s a step first of all when we submit it and the agency looks at the file, and this is similar to the process in Canada where they basically look to see whether the file is complete,” he says. “And we know that within 60 days of the submission they need to make a judgement as to whether or not the file is complete to permit a substantive review.

“Once that happens,” Szpunar continues, “we expect often to get a comment within 75 days in terms of what their initial impressions are. Ultimately, though, the big time clock that you look at is 10 months following that submission — (that) is when the FDA is obligated to give you an action.”

That action, he says, can be approval, non-approval or approvable status, where additional data are required or some questions need answering before the process can go forward.

Key Relations

Biovail’s four NDAs from last year passed that first step, Szpunar says, and were accepted for review. Last November, the company received an approvable letter for one of those four NDAs, for its pain medication Ralivia ER™. Szpunar says for a firm to conduct successful FDA interactions, having its own regulatory affairs team with extensive knowledge of interacting with the agency is key.

“Honestly, that’s not different really than the way it is in Canada either,” he says. “Our relationship with the TPD, which I would describe as equally as good and productive is also, in many cases, predicated on the fact that we’ve got a very experienced reg. group.”

Having that expertise and capability in-house — in both the U.S. and Canada — has established the firm’s credibility and track record with both the FDA and the Therapeutic Products Directorate (TPD) in Canada, Howling says, and this has helped the firm in moving forward with both regulatory bodies.

Biovail deals with existing compounds — to which the firm is aiming to provide “a clinical, meaningful enhancement benefit” — that have been previously approved by the FDA or by the TPD, Howling says. For this reason, these compounds have “been proven to be safe, they’ve been proven to be efficacious, they’ve been in the marketplace typically for years,” he says.

Common to big pharma, and a plan that Biovail has adopted, is to file its products simultaneously in as many world markets as possible, Szpunar says, barring possible factors such as exclusivity periods. “We typically try to keep Canada and the U.S. on a same track,” he says. “Now the review times are different — typically reviews take much longer in Canada. But in terms of submissions, we’re typically filing parallel paths.”

In working toward approvals, Szpunar says he’s always found that developing a collegial relationship with the regulatory bodies has been the most productive route.

“In the end, the goals of our company and the goals of the regulatory agencies are the same,” Szpunar says. “We all, I think, are in the areas that we’re in because we wanted to promote human health and the good of mankind . . . So, I think we both approach our jobs with the same goals and appreciation for where each other sits. And as long as you do that, you’re better off.”