Although often overshadowed by the novelty of FDA’s sweeping authority in constructing Risk Evaluation and Mitigation Strategies, examination of agency review documents suggest that the FDA Amendments Act’s other safety innovation, granting FDA the ability to require (i.e., enforce) post-marketing studies, is increasingly important to the approval of NDAs with marginal data on issues of concern.

FDA review documents – the memoranda, minutes, reviews and administrative record of an application’s path through the agency – can serve as case studies of the agency’s acclimatization to stress and change. In 2010, Pharmaceutical Approvals Monthly's drug review profile features illustrate how the agency is adjusting to its new powers under the FDA Amendments Act (see chart).

The introduction of Risk Evaluation and Mitigation Strategies has been the headline new FDA authority. But based on the drug review profiles of 2010, the agency’s new power to require post-marketing studies – instead of being limited to negotiating voluntary commitments – is emerging as an important tool on its own account.

At the same time, FDA appears to be pulling back from aggressive use of REMS. While 40% of all original NDA approvals from March 2009-March 2010 had REMS, the proportion dropped to 30% in the next six months, according to analysis by Elsevier Business Intelligence’s RPM Report (Also see "REMS 2.0: FDA Refining New Drug Safety Tools" - Pink Sheet, 1 November, 2010.).

FDA’s November approval of Theratechnologies’ Egrifta (tesamorelin) illustrates the pullback. Despite a REMS submitted by the sponsor, FDA approved the HIV lipodystrophy drug without it, prescribing instead PMRs for an observational study and a trial to further assess specific risks (“Egrifta Approval Suggests Evolution In FDA Thinking On Role Of REMS,” “The Pink Sheet,” Nov. 29. 2010). [Editor's note: Egrifta will be the subject of a coming drug review profile.]

REMS are most suitable for known risks, whereas PMRs can be helpful in uncertain situations.

Where REMS Are Best

REMS are most suitable for products with known safety issues. Post-marketing requirements allow FDA more control in more uncertain situations, notably when the agency still needs to determine if there is a risk. A sizable portion of new molecular entities, of course, present FDA with overlapping conundrums: of the 15 new molecular entities approved in 2010, four have REMS programs – and all four also have post-marketing requirements ([A#06110101030]).

And PMRs, which address a broader range of issues with a greater variety of approaches, are much more widely used than REMS. Indeed, 12 of the 15 NME approvals in 2010 carried PMRs.

REMS are especially important in cases where FDA is struggling to balance safety concerns with medical need. Agency review documents show the risk management programs providing a keystone of the post-marketing safety infrastructure for drugs like Theravance’s antibiotic Vibativ (telavancin) and Novo Nordisk’s antidiabetic Victoza (liraglutide), allowing new drugs onto the market to meet important medical needs while communicating serious risk information that in a pre-FDAAA era might have precluded approval.

For Vibativ, the REMS provided a solution to internal FDA disagreement (Also see "FDA Found Answer To Vibativ Dilemma Of Teratogenicity Vs. Microbial Resistance In REMS" - Pink Sheet, 1 January, 2010.). For Victoza, the REMS process facilitated a communication plan to ensure awareness of liraglutide’s thyroid cancer risk and pancreatitis, a class concern, clearing the way to approval of what FDA officials highlighted as a much-needed new diabetes therapy option with a clear demonstration of benefit (Also see "FDA's Victoza Decision BalancedUnknown Cancer Risk Against Known FDAAA Measures" - Pink Sheet, 1 February, 2010.).

The communication plan tools in REMS have turned out to be a way to better ensure proper patient selection. REMS for Vibativ and Sanofi-Aventis’ Multaq (dronedarone) allowed FDA to reinforce labeling’s patient eligibility limits with additional communication efforts. Vibativ is not to be used in women who are or might become pregnant due to teratogenicity signals; Multaq’s REMS has unusually extensive communication elements to explain to practitioners that the drug is not to be used in patients with severe heart failure. Novartis’ REMS for Zortress (everolimus) focuses on mitigation of risks, including the potential for renal impairment if the drug is administered with standard doses of cyclosporine.

REMS have proved useful in other ways. The program for Acorda’s Ampyra (dalfampridine) addresses the MS agent’s unusual history for an NME, in addition to safety concerns. FDA took pains to inform potential prescribers that the approved drug formulation, a sustained-release tablet that carries a reduced risk of seizures, is not substitutable for the immediate-release pharmacy-compounded versions that had long been in use.

Pivotal Post-Marketing Requirements

But for a drug like Takeda’s Uloric (febuxostat), it was FDA’s new ability to require post-marketing studies that swung the pendulum toward approval. Despite Uloric’s long and troubled regulatory odyssey, FDA found that a REMS was not necessary. The agency’s concerns did not center on how to mitigate a suspected risk; the agency needs to know if the risk is really there. After three review cycles, Uloric was approved with a required post-marketing cardiac outcomes study (Also see "Score One For FDAAA: Uloric Approval Was Clinched By Post-Market Powers" - Pink Sheet, 1 July, 2010.).

Some types of studies, such as those looking for very rare events or observational and other long-term monitoring investigations, are simply not feasible in the pre-market setting.

Victoza’s PMRs include thyroid cancer studies that could not be conducted pre-marketing because of the rarity of the concern. HRA Pharma’s emergency contraceptive ella (ulipristal) has PMRs for observational studies in difficult-to-recruit populations: tracking pregnancy outcomes in the few women whose pregnancies are not successfully averted by ella and an adolescent clinical monitoring study, which is difficult to recruit for because of the young age of the subjects (Also see "HRA’s Efficient Ella Development Strategy Begat FDA’s Efficient NDA Review" - Pink Sheet, 1 November, 2010.)

Of course, PMRs are also useful for regulatory due diligence to ensure that all the scientific “I”s are dotted and “T”s are crossed, as in the six PMRs Ampyra has in addition to its REMS.

The Only Constant Is Change

The advent of FDAAA shook up the regulatory landscape in highly visible ways. But sponsors have always had to deal with a shifting firmament of evolving scientific knowledge and regulatory refinements. New guidance documents from FDA on trials for antibiotics and assessment of cardiovascular risk in diabetes trials, for example, reset the rules for major drug categories.

Some of the biggest delays can come from shifting sands at FDA, or external changes that impact a drug review.

Despite the best efforts of sponsors and regulators to prospectively define standards for success in clinical trials, the degree of difficulty can dramatically increase with new information, events, or changes in clinical practice.

The impact of the continuing evolution of medical and regulatory practice on applications was one common thread in the 2010 series of Pharmaceutical Approvals Monthly’s Drug Review Profiles.

Sometimes the impact of external changes on a drug review is dramatic. Sanofi-Aventis ancestor Sanofi-Synthelabo first submitted the dronedarone NDA in 2005, positioning it as the successor to the then-recently generic blockbuster anti-arrhythmic amiodarone. Just one month before NDA submission, FDA had warned of serious and even fatal adverse events with the older product – focusing FDA reviewers' attention on toxicity, given dronedarone’s structural similarity to amiodarone.

The second review cycle for Dendreon’s autologous cancer vaccine Provenge (sipuleucel-T) took place in an environment of increased scrutiny when a publicity maelstrom followed the agency’s “complete response” letter. The review proceeded in an atmosphere of heightened expectations and caution (Also see "Provenge Panel's Uncertainty Was More Persuasive To FDA Than Its Vote" - Pink Sheet, 1 June, 2010.).

The anti-diabetic Victoza was also reviewed under an unusually high level of public interest given the emergency of cardiovascular safety signals with marketed anti-diabetics.

Novartis’ Zortress was under review for kidney transplant rejection when FDA approved another drug in its class, Pfizer’s Rapamune (sirolimus), with a novel dosing regimen that allowed for reduced dosing of cyclosporine and, therefore, less renal toxicity. The advance changed FDA’s threshold for accepting Zortress’ safety profile. FDA told Novartis that “the previous era … was no longer relevant to the current transplant community’s view on renal toxicity.”

Sometimes it is more subtle. Acorda’s Ampyra development program was notable for its novel indication based on a novel type of responder analysis that FDA reviewers had to come to terms with (Also see "Acorda's Novel Primary Endpoint For Ampyra Was Made Possible By A Supporting Scaffolding Of Secondary Analyses" - Pink Sheet, 1 April, 2010.).

And sometimes new events are just a hiccup in the review. GlaxoSmithKline and Genmab’s Arzerra (ofatumumab) was under review for accelerated approval in a niche oncology indication in refractory chronic lymphocytic leukemia when a new CLL therapy was approved. FDA took time to evaluate the impact of the new drug, but determined that the new drug, Cephalon’s Treanda, would not be a satisfactory alternative in the highly refractory population Arzerra was seeking to treat (Also see "Context Is Key To Accelerated Approval In Oncology, Arzerra Review Shows" - Pink Sheet, 1 September, 2010.).

FDA’s new guidance on antibiotic development, which up-ended the anti-infective field with its new approach to non-inferiority, was addressed during the Vibativ review, but did not become an issue because the NI margin was not a problem in the Vibativ trials (“Low Non-Inferiority Margin Meant Smooth Sailing For Vibativ Efficacy Review,” Pharmaceutical Approvals Monthly, January 2010).

The Value Of Expertise

In the ever-more complex regulatory and scientific environment, the value of expertise is increasingly apparent. FDA extensively sought consultants, from in-house groups like the Maternal Health Staff or colleagues in other divisions with specific expertise.

“In the absence of rigorous data … the decision rests on an informed speculation by experts in the field,” Arzerra Cross-Disciplinary Team Leader Joseph Gootenberg said of the small dataset for the oncologic (Also see "When Hard Data Are Sparse, FDA Looks To The Experts" - Pink Sheet, 1 September, 2010.).

To come to grips with the Vibativ teratogenicity signal, the review team turned to the consulting group for pediatric and maternal health, one of a few teams of specific experts at FDA who handle specialized topics. The review team for Uloric, faced with a potential signal of cardiovascular effects, was reassured by consults from the Division of Cardiovascular and Renal Products.

However, sometimes the existence of many experts under one agency roof can cause friction. During the Provenge review, for example, tensions between CDER and CBER became apparent (“CDER vs. CBER: Consulting As Usual, Or Hints Of Inter-Center Power Struggle?” Pharmaceutical Approvals Monthly, June 2010).

Sponsors also look for external expertise, especially smaller or foreign companies new to navigating FDA's waters. Contract research organizations and law firms offer such assistance, taking part in notable regulatory resuscitations like Vanda’s all-but-dead antipsychotic Fanapt (iloperidone). Among the 2010 approvals class, Theratechnologies’ troubled HIV lipodystrophy agent Egrifta (tesamorelin) was shepherded to approval by Kendle International. Orphan Europe’s Carbaglu (carglumic acid) was handled by R&R Registrations and Merz’ Xeomin (incobotulinumtoxinA) BLA was supervised by the Biologics Consulting Group. The CRO Target Health guided the ella application to a smooth, first-cycle approval.

Industry has been calling for more meetings with FDA, which would give a boost to less-experienced companies that now turn to CROs and the like, sometimes after lots of time has been wasted. This call by industry for more meetings and more communication with FDA has been playing out in the ongoing negotiations over upcoming PDUFA reauthorization (Also see "FDA Floats 15-Month Review Timeline For PDUFA V; Firms Mull Tradeoff On Speed Vs. Certainty" - Pink Sheet, 13 December, 2010.).

But while industry wants more chances to communicate with FDA, the experience set forth in the drug review documents suggests that what industry may need to do most is to listen.

When FDA Speaks, Sponsors Should Listen

Tempting as it may be to find an end-run around burdensome FDA recommendations, the experience of three large sponsors discussed in drug review profiles in 2010 emphasizes that ignoring the agency’s advice is a prescription for long, expensive, multi-cycle reviews.

Despite substantial – and successful – regulatory experience, Sanofi-Aventis, Takeda and Novartis ended up with extremely long reviews after trying, and failing, to evade FDA recommendations. The review of Sanofi-Aventis’ Multaq took 49 months from original submission to approval, Takeda’s Uloric took 50 months to approval, and Novartis’ Zortress took over seven years (88 months) and four review cycles before finally being cleared for marketing.

Novartis spent two review cycles trying to convince FDA that a new, safer dosage regimen for the kidney transplant agent Zortress could be justified by data from pivotal trial extensions or uncontrolled trials, despite the agency’s clear advice during pre-NDA meetings that doing so would be problematic. And thus, when Novartis responded to the first “approvable” letter’s call for a prospective controlled study with two uncontrolled studies, FDA produced another action letter. Novartis ultimately conducted and submitted a prospective study after, arguably, wasting two review cycles (Also see "Zortress Approval Delay Caused By Novartis Attempts To Avoid Controlled Trial Of Dosing Regimen" - Pink Sheet, 1 October, 2010.).

Some of the best advice for sponsors is to follow FDA's suggestions the first time around – because the agency may hold out for that data later on.

Takeda tried to avoid conducting a new trial of its gout drug Uloric even though FDA recommended another safety trial to address the risk of cardiovascular side effects in its first “approvable” letter. Takeda instead chose to submit re-adjudication of the original data, only to receive another action letter. The letters also called for a lower dose to be studied. Three years after the first action letter, Takeda resubmitted the NDA with an additional Phase III safety study using a lower dose – and received approval ("Did Takeda Make The Right Decisions Throughout The Uloric Review?" Pharmaceutical Approvals Monthly, July 2010).

Multaq’s four-year review odyssey took some winding paths as Sanofi-Synthelabo failed to incorporate FDA concerns about issues both broad (questioning the value of the drug’s modest efficacy and the assumption that reductions in ventricular rate would lead to symptomatic improvement) and specific (the sponsor’s intransigence on dosing, persisting with a fixed dose in the face of repeated urging by FDA to study a dose range and ignoring FDA’s request for studies at a lower dose level). A “not approvable” letter recommended a trial in patients with underlying heart disease, but Sanofi-Aventis chose to conduct a study excluding advanced heart disease patients. In the end, Sanofi had to file a new NDA for a new claim.

The silver lining of these drawn-out reviews is that FDA does provide consistent guidance to sponsors. If sponsors can consistently incorporate the agency’s comments, then industry’s calls for increased communication could make reviews faster and more efficient. And the experience of some of the smaller sponsors suggests that in the complicated world of drug regulation, hiring a guide who knows how to listen and how to respond may be one of the smartest moves you can make – especially in an era of regulatory change.

By Bridget Silverman

Out Of The Shadow Of REMS: FDA Review Documents Show Emerging Importance Of Post-Marketing Requirements

More from Archive

More from Pink Sheet