Allergan's suit against FDA seeking a court ruling that it can provide physicians with information on unapproved uses of Botox is another milestone in the debate over off-label promotion, but it also may be the first legal indication of the power of Risk Evaluation and Mitigation Strategies to impact sales.

Allergan filed a motion for a preliminary injunction on Oct. 1 to enjoin the government from applying provisions of the Food, Drug, and Cosmetic Act and FDA regulations that restrict its speech on off-label drug use. The company also filed a same-day complaint requesting a declaratory judgment that the restrictions as applied to Botox are an unconstitutional violation of its First Amendment rights.

During an Oct. 2 conference call, Douglas Ingram, Allergan's executive vice president and chief administrative officer, said the complaint was relevant now given the REMS that FDA requested in April and approved at the end of July.

The REMS requires Allergan to communicate to physicians the risk of swallowing and breathing difficulties in children and adults treated for spasticity, an unapproved indication. FDA ordered every manufacturer of botulinum toxin to implement a REMS and add a boxed warning to their drug labeling about the risk, and to change their generic names ('The Pink Sheet' DAILY, April 30, 2009).

At the time, many saw the REMS and the additional safety measures as a potential boon for Allergan, discouraging substitution with cheaper botulinum competitors and giving the company a clinical, not simply a cosmetic, story to talk to doctors about.

But Allergan has apparently concluded that the ability to get doctors' attention isn't very helpful if the REMS ends up dampening worthwhile use of the drug.

The REMS could end up discouraging use of the firm's key product in a new indication before the firm even has a chance to begin promoting it. And so Allergan wants to be able to provide physicians with information on how best to treat patients for spasticity.

CEO David Pyott said Allegan faces "a real dilemma" in the breadth of Botox's use. He noted that the spasticity indication has been approved virtually everywhere in the world over the last 10 years. In August 2008, Allergan submitted a supplemental biologics license application to FDA for use of Botox to treat adults who suffer from upper-limb spasticity after stroke. The agency issued a "complete response" letter in May requesting Allergan provide additional details about certain clinical trials and conduct a post-approval study in pediatric patients ages two to 17.

If FDA approves the new indication quickly, the suit would essentially be moot, since Allergan would presumably then be free to talk about the drug's benefits. The court case could reflect concern from the company that approval is a long way off.

Botox is approved for treatment of neuromuscular disorders, including crossed eyes, spasm of the eyelids, involuntary neck muscle contractions and excess underarm sweating. The drug had sales of $1.3 billion in 2008, representing approximately 30 percent of the company's revenue.

Putting The Risk In Context

Ingram said it was unusual for a REMS program to require communication about off-label use. "If we are to speak of off-label use, it is important to proactively provide comprehensive information about off-label uses," he said.

"The boxed warning and REMS materials identify the risk of potential distant spread of toxin effect, but they do not give physicians using Botox for spasticity specific guidance about how to further minimize that risk while still obtaining an acceptable therapeutic effect," Allergan states in a memorandum of law in support of its motion for a preliminary injunction.

The risk may be affected by such factors as the dose used at a given injection site, the number and location of injections sites, the frequency of treatment, injection technique, and patient selection, the memo notes, and Allergan would like to be able to explain that to physicians.

However, "a proactive dialog of that nature would place Allergan at an untenably high risk of government enforcement," Ingram said.

Allergan Chilled By U.S. Attorney Loucks' Comments

Allergan's complaint follows a wave of hefty settlements by pharmaceutical companies over their off-label marketing practices. The suit cited Lilly's $1.4 billion settlement to resolve charges of off-label promotion of Zyprexa (olanzapine) and Pfizer's $2.3 billion settlement of allegations of off-label marketing of several drugs and kickbacks to health care providers (Also see "Pfizer's Record-Breaking $2.3 Bil. Settlement With U.S. Attorney Imposes New Restrictions on Corporate Behavior" - Pink Sheet, 7 September, 2009.).

Allergan said the government's interpretation of statutes and regulations has chilled manufacturers' speech to medical professionals. Allergan quoted a statement made by Michael Loucks, acting U.S. Attorney for the District of Massachusetts, at a press conference announcing the Pfizer settlement. Loucks said: "Any indication not on the label is off-label, and selling an approved drug intending that it be used for an off-label use is a violation of the law."

Allergan already is facing government scrutiny of its marketing practices. In March 2008, the U.S. Attorney's Office in the Northern District of Georgia subpoenaed the company for documents relating to past sales and marketing practices related to Botox. Ingram emphasized that the investigation involves past practices.

Court Could Order FDA To Issue Guidance

The company's pre-emptive suit against the government is unusual. But one attorney said Allergan might succeed in getting FDA to provide more guidance on the use of off-label information.

"This is a fascinating complaint," said Meredith Manning, a partner at Hogan & Hartson. "I'm very sympathetic to the fact pattern." She said Allergan explained in its suit that off-label use is widespread, that there are clinical studies for Botox's use in spasticity, that it has negotiated with FDA, that it knows doctors are using the drug for off-label indications and that it has data on how to make such use safer.

Manning, a former assistant U.S. attorney and former associate chief counsel at FDA, said she wouldn't be surprised to see the court tell FDA to issue some guidance so Allergan can make available some data on safe use of the drug for unapproved indications. But she does not think a sweeping ruling that strikes down misbranding regulations is likely.

FDA just issued its first draft guidance on REMS issues, discussing the format of submissions and the timing of assessments but leaving a host of questions unanswered ([A#1409093002]).

Richard Samp, of the Washington Legal Foundation, said case law is on Allergan's side. His group filed suit against FDA a decade ago claiming its prohibition on dissemination of journal reprints violated the First Amendment. A district court granted a preliminary injunction against the agency but FDA withdrew its appeal and a portion of the injunction was declared moot.

"How far [that ruling] extends has never been tested," Samp said.

PhRMA Also Seeking Off-Label Assurance

During the conference call, an analyst asked how much of a factor Pfizer's settlement was in Allergan's decision to file suit. Ingram said he could not comment on that, but noted Allergan's complaint relates only to truthful, non-misleading statements.

Another caller asked if the company had worked with another organization, such as the Pharmaceutical Research and Manufacturers of America or the Washington Legal Foundation, in preparing its complaint. Ingram said Allergan had not worked with any third party. "We are not interested in being crusaders," he said. This is "unique to our product."

PhRMA has separately sought assurances from FDA that it was okay to provide off-label information in another context. The association sent a letter to the National Institutes of Health in April saying companies should not have to submit summaries of clinical trials to the government database clinicaltrials.gov until FDA issued guidance on what would constitute unlawful promotion of products for unapproved uses (Also see "Pharma Firms Want Protection From FDA Actions When Listing On ClinicalTrials.Gov" - Pink Sheet, 20 April, 2009.).

Who Controls a REMS?

While the question of off-label promotion is central to the Allergan case, it also opens up the question of how much authority FDA has to dictate the safety profile that a firm presents about its products. The 2007 legislation that created REMS gave FDA several other safety powers, including the ability to change a product's label without a sponsor's permission.

By establishing a spasticity REMS, FDA essentially concluded that the risk to patients from the off-label use outweighs any benefit the treatment may provide. Allergan's suit is essentially saying that the agency got the risk-benefit balance wrong in this case, and if the courts agree, that might broadly curtail FDA's new safety powers.

-Brenda Sandburg (b.sandburg@elsevier.com)

Allergan's Freedom From Expression Suit Challenges Gov't REMS, Off-Label Powers

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