Two Center for Drug Evaluation and Research advisory committees that were eliminated a decade ago appear primed to make a comeback in 2013, with the agency hinting it will resuscitate its Pharmacy Compounding Drugs Advisory Committee in the new year and the inaugural meeting of the newly re-formed Medical Imaging Drugs Advisory Committee set for February.

Re-establishment of a compounding drugs panel, which was dissolved in 2002, would give the agency a scientific public forum, and perhaps some political cover, for addressing issues such as quality control and drug shortages that have received widespread attention with the fungal meningitis outbreak related to the New England Compounding Center’s steroid injections.

The full Drug Safety and Risk Management Advisory Committee has convened less frequently as the public and legislative focus has shifted from post-marketing safety to pharmaceutical innovation.

While FDA is seemingly interested in its outside experts’ views on compounded drug safety, it continues to rely less on its full Drug Safety and Risk Management Advisory Committee for input on NDA/BLA approvals, risk management plans and post-approval safety issues. The panel as a whole met for only two days in 2012, although individual committee members participated in more than a dozen other meetings.

The reduction in DSARM’s workload is perhaps expected given the shifting legislative and public focus from drug safety, which led to the 2007 FDA Amendments Act, to an emphasis on pharmaceutical innovation and speeding novel therapies to market, as reflected in the 2012 FDA Safety and Innovation Act. The agency also appears more comfortable managing FDAAA’s safety provisions, including Risk Evaluation and Mitigation Strategies and post-marketing safety requirements, on its own without the need for outside input.

Although CDER brought more products up for external review than in 2011, it also approved a higher percentage of new molecular entities and novel biologics that had not been vetted by its advisors – a trend that is understandable given the near-record number of novel products that cleared the drugs center in 2012.

The Oncologic Drugs Advisory Committee continued to be a workhorse among CDER’s committees, which is not surprising given that cancer/hematology-related indications accounted for almost 40% of the 39 novel products approved in 2012 Also see "Oncologics Drove FDA’s 2012 Novel Approval Count To 15-Year High" - Pink Sheet, 7 January, 2013.. However, less than half of ODAC’s workload involved the review of NMEs, suggesting the oncology review division may be more inclined to seek outside advice on supplemental indications or new formulations of existing treatments that present a different, and less favorable, risk/benefit equation than seen with the original approval.

Compounding Issues Becoming A Priority …

FDA has made no formal announcement that it is reconvening its Pharmacy Compounding Drugs Advisory Committee, but there are strong indications this group is being re-established and will see work in 2013 Also see "FDA’s Advisory Committee Schedule Hints At Re-formulated Compounding Panel" - Pink Sheet, 4 January, 2013..

The agency’s tentative schedule of advisory committee meetings, published Jan. 2 in the Federal Register, includes the compounding panel in its listing of CDER committees, with tentative meeting dates “if needed, to be determined.” CDER’s website lists 13 vacancies on the compounding panel, the function of which is to provide advice on scientific, technical and medical issues concerning drug compounding by pharmacists and licensed practitioners.

The compounding panel originally was established through the FDA Modernization Act of 1997 as part of a section that exempted some compounded drugs from new drug approval and good manufacturing practice requirements. A federal appeals court ruled that certain speech-related provisions of that section were unconstitutional, bringing down the entire section. In April 2002, the Supreme Court essentially upheld the appeals court’s ruling Also see "Supreme Court Reaffirms Least Restrictive Standard For Ad Controls" - Pink Sheet, 6 May, 2002..

FDA announced the compounding drugs panel’s termination, along with that of the Medical Imaging Drugs Advisory Committee, in November 2002. The General Accounting Office and the General Services Administration had suggested eliminating the committees because they met infrequently Also see "FDA Advisory Committee Line-Up Shrinks With Elimination Of Two Panels" - Pink Sheet, 25 November, 2002..

Re-forming the compounding committee would not be a first for the agency. The medical imaging drugs panel was re-established in May 2011. Although the group did not meet in either 2011 or 2012, it is slated to convene Feb. 14 to review Guerbet SA’s gadoterate meglumine injection for magnetic resonance imaging of the brain, spine and associated tissues Also see "Guerbet Looks To Separate Dotarem In Crowded Contrast Agent Market" - Pink Sheet, 3 January, 2013..

Before the compounding committee was dissolved, it focused on assessing drugs for inclusion or exclusion from a list of bulk drugs permitted for pharmacy compounding Also see "FDA To Facilitate 4-AP Compassionate Use INDs For MS, Axelrad Says" - Pink Sheet, 24 July, 2000..

Re-establishing the group would give CDER officials an opportunity to publicly air concerns specific to particular active pharmaceutical ingredients as well as more general issues related to compounded drugs, such as the impact that drug shortages, particularly sterile injectables, have had on the growth of compounding and how stepped-up enforcement might exacerbate such shortages.

… While Post-marketing Safety Needs Less AdComm Attention

In 2011, CDER devoted fewer meeting days to product approvability issues and more attention to topic-oriented discussions, such as class-wide safety issues, clinical trial design and general drug development matters Also see "FDA Approving More Novel Drugs Without Advisory Committee Review" - Pink Sheet, 23 January, 2012.. However, this was not the case in 2012, which saw not only more meeting days for CDER’s committees (49, compared to 43 in 2011) but also an increased proportion of meeting days dedicated to product-specific approval reviews.

In 2011, fewer than half of all CDER advisory committee meeting days were taken up by NDA/BLA reviews. In contrast, 70% of all 2012 meeting days were dedicated to the approvability of a new product or supplemental indication (see chart).

AdComm Meeting Days By Subject Matter

Data compiled from FDA website

DSARM’s meeting-day count in 2012 was its lowest since 2003, when the full panel met only one day. The drug safety panel became a standalone committee in 2002.

In 2012, DSARM convened for a two-day session in December focused on risk management strategies for teratogens. The panel’s total for the year would have doubled had an Oct. 29-30 session on hydrocodone-containing products not been postponed by Hurricane Sandy. That meeting has been rescheduled for Jan. 24-25.

However, even if the hydrocodone meeting had gone on as planned, DSARM still would have fallen short of its total number of meeting days in 2011 (six) and well off the 13-day mark of 2010, when the agency was still adjusting to its new authorities under FDAAA Also see "Where FDA Is Paying The Most Attention: Drug Safety Advisory Committee Had The Most Meetings In 2010" - Pink Sheet, 10 January, 2011.. The committee’s work that year included a two-day cardiovascular safety review of GlaxoSmithKline PLC’s diabetes drug Avandia (rosiglitazone) and several days of meetings on safety issues with pain agents. The committee was also asked to consider three NDAs for approval in pain indications and fibromyalgia.

In contrast, the full committee was not convened to consider an NDA approval in either of the past two years. Rather than polling the entire panel on such issues, the agency has increasingly asked individual DSARM representatives to sit as special government employees on other committees. In 2012, DSARM members participated in 14 other committee meetings, 11 of which involved product approval issues.

NMEs Vs. Supplemental Uses

Given the increased percentage of AdComm meeting days dedicated to product approval decisions and CDER’s high NME/novel biologic approval total for 2012, it is perhaps surprising that so many meetings focused not on innovative new drugs, but rather on supplemental indications or new formulations of existing drugs. Approximately half of all meetings dedicated to product-specific issues involved NMEs or novel biologics (see chart).

AdComm Reviews Of Novel Vs. Non-novel Products

Data compiled from FDA website

Among the higher-profile supplemental uses considered by FDA’s panels were a pre-exposure prophylaxis indication for Gilead Sciences Inc.’s HIV treatment Truvada (emtricitabine/tenofovir) and use of Janssen Pharmaceuticals Inc.’s anticoagulant Xarelto (rivaroxaban) in acute coronary syndrome patients. Truvada for PrEP was endorsed by the Antiviral Drugs Advisory Committee during a meeting that ran more than 12 hours, while the Cardiovascular and Renal Drugs Advisory Committee gave a thumbs-down to Xarelto due to concerns about missing data in the pivotal ATLAS trial.

2012 also marked the third straight year that the percentage of approved novel products that have undergone panel review has fallen, despite FDAAA’s emphasis on taking novel products through the advisory committee process. Of the 39 NMEs/novel biologics approved by CDER, only 16 (41%) received panel consideration.

ODAC, EMDAC See The Most Action

Just as the oncology/hematology review division led the way with the largest number of NME/novel biologic approvals within CDER at 14, ODAC ranked among the busiest of the drugs center’s committees.

The oncology panel met for a total of eight days – a mark equaled only by the Endocrinologic and Metabolic Drugs Advisory Committee – and considered seven products (see chart). However, only three of the oncology agents it reviewed were potential NMEs: Merck & Co. Inc./Ariad Pharmaceuticals Inc.’s mTOR inhibitor Taltorvic (ridaforolimus) for sarcoma; Sanofi’s low molecular weight heparin semuloparin for prevention of venous thromboembolism in cancer patients; and Onyx Pharmaceuticals Inc.’s second-generation proteasome inhibitor Kyprolis (carfilzomib) for multiple myeloma.

Carfilzomib was the only one of the three to garner ODAC’s endorsement and FDA approval. The ridaforolimus filing resulted in a “complete response” letter, and Sanofi withdrew the semuloparin NDA following ODAC’s negative review ([A#14120709002]).

Of the other four products reviewed by ODAC encompassing new indications or new formulations of existing therapies, the panel gave its blessing to two of them: a sarcoma indication for GSK’s Votrient (pazopanib) and approval of Talon Therapeutics Inc. ’s Marqibo, a liposomal form of vincristine, for acute lymphoblastic leukemia. The committee recommended against expanded indications for Amgen Inc.’s Xgeva (denosumab) for prolonging bone metastasis-free survival in men with castrate-resistant prostate cancer, and use of Eisai Co. Ltd.’s Dacogen (decitabine) in newly diagnosed acute myelogenous leukemia patients.

Among the Office of Hematology and Oncology Products’ 14 novel approvals, only four received AdComm vetting at any point. One of those, Teva Pharmaceutical Industries Ltd.’s leukemia drug Synribo (omacetaxine mepesuccinate), originally was submitted as a personalized medicine product and received a negative ODAC review in March 2010, which led to a “complete response” letter. The product was resubmitted under a new NDA in March 2012 for a later-stage indication and without a personalized claim.

In a Jan. 4 note, the health care policy analysis firm Prevision Policy noted that the best cancer drugs are moving through the agency in three or four months without stopping by ODAC, and the committee generally is convening only for those applications that fall short of clear breakthrough potential.

In contrast to ODAC, the Endocrinologic and Metabolic Drugs Advisory Committee was more bullish about the drugs on its plate, endorsing all six of the new products it reviewed. These included two new obesity drugs, Arena Pharmaceuticals Inc.’s Belviq (lorcaserin) and Vivus Inc.’s Qsymia (phentermine/topiramate), which each made their second trip to the committee in three years. The panel also endorsed two novel treatments for homozygous familial hypercholesterolemia – Aegerion Pharmaceuticals Inc.’s Juxtapid (lomitapide) and Genzyme Corp.’s Kynamro (mipomersen) – as well as Novartis AG’s Cushing’s disease treatment Signifor (pasiretoide) and Novo Nordisk AS’ novel long-acting insulin degludec products Tresiba and Ryzodeg. [See online chart [A#00130114007]for a full listing of advisory committees’ product-specific approval recommendations in 2012.]

[Sidebar#00130114007]

Overall, CDER’s committees recommended approval of approximately two-thirds of the products reviewed. The agency’s concordance with those recommendations remains high. Of 39 recommendations related to new drug approvals, new indications or labeling changes, the agency has taken a publicly disclosed action on 31 of them, 28 of which were aligned with the committees’ advice, for a concordance rate of 90%.

[Editor's note: Data on the number of agency actions and concordance rates were updated after initial publication of this story to reflect an approval that occurred late in the year.]

Contrary to the approval recommendations of its advisory committees, CDER issued “complete response” letters on two occasions. Those decisions involved Chelsea Therapeutics International Ltd.’s orthostatic hypotension drug Northera (droxidopa) and Pfizer Inc.’s Vyndaqel (tafamidis meglumine). On the latter drug, which accounted for the Peripheral and Central Nervous System Drugs Advisory Committee’s only meeting of the year, the panel voted against full approval in treating transthyretin familial amyloid polyneuropathy but found the data supported accelerated approval based on a surrogate marker.

FDA actions related to seven other product-specific recommendations are either pending or not publicly disclosed; in the case of Sanofi’s VTE prophylaxis agent semuloparin, the NDA was withdrawn before agency action on the committee’s recommendations.

NDA/BLA withdrawals after the sponsors received the agency’s negative briefing book led to the cancellation of several meetings in 2012.

Drug application withdrawals prior to a scheduled advisory committee meeting, but apparently after the sponsor had received the agency’s briefing book, led to the cancellation of several meetings.

Two of the withdrawn applications were scheduled to go before ODAC – CTI BioPharma Corp.’s Pixuvri (pixantrone) for non-Hodgkin’s lymphoma and GSK’s Tykerb (lapatinib) for combination use with Roche’s Herceptin (trastuzumab) for HER2+ metastatic breast cancer patients who received prior trastuzumab therapy. Two others were to be considered by the cardio-renal committee – Shire Human Genetic Therapies Inc.’s Replagal (agalsidase alfa) for Fabry disease and Novartis’ imatinib for pulmonary arterial hypertension.

In announcing that it had withdrawn the Replagal BLA two weeks before the scheduled meeting, Shire said recent dialogue with FDA suggested additional controlled trials would be required before approval. As a result, the company said, it did not intend to continue to develop Replagal for the U.S. market.

However, Shire’s press release prompted a highly unusual, and even defensive, rebuttal from FDA, which generally does not comment on pending or withdrawn applications and often provides only vague reasons for cancelling an advisory committee meeting. FDA said it encouraged Shire to submit the BLA so it could review all available data, and the agency had not made any decision ahead of the committee meeting as to whether additional studies would be needed Also see "Shire Withdraws Replagal BLA Rather Than Conduct Lengthy Trials – Updated" - Pink Sheet, 15 March, 2012..

What’s Ahead For 2013?

While it remains to be seen how active the new Pharmacy Compounding Drugs Advisory Committee will be in 2013, some CDER committees, such as the medical imaging drugs panel, are on target to meet or exceed their 2012 workload in the first few months of the year alone.

The Pulmonary-Allergy Drugs Advisory Committee met only once in 2012 to consider approval of Forest Laboratories Inc.’s Tudorza Pressair (aclidinium bromide) for chronic obstructive pulmonary disease. However, the panel already is scheduled to meet three times through early March to consider two new COPD agents, Boehringer Ingelheim GMBH’s Striverdi Respimat (olodaterol) and GSK’s Breo Ellipta (fluticasone furoate/vilanterol), as well as Pharmaxis Ltd.’s cystic fibrosis drug Bronchitol (mannitol).

Also facing advisory committee review in the new year are two non-hormonal products for treatment of menopause-related hot flashes; both Depomed Inc.’s Serada (gabapentin) and Noven Pharmaceuticals Inc.’s Mesafem (paroxetine mesylate) will be considered by the reproductive health drugs panel on March 4.

FDA and its stakeholders will be looking to see whether, and how, the new review model that began Oct. 1 for newly filed NMEs and novel biologics impacts the advisory committee process.

The new program was negotiated pursuant to the Prescription Drug User Fee Act reauthorization and is aimed at improving the efficiency of the first-cycle review. It extends the user fee goal dates for priority and standard reviews by two months but also provides for increased communication between FDA and the sponsor during the course of a review.

The increased communication built into PDUFA V’s new review model for NMEs may reduce the number of NDA withdrawals on the eve of an AdComm review.

These communication tools include discussion in the 74-day letter about preliminary plans on the need for an AdComm. A new mid-cycle communication will include an update from FDA to the sponsor on any plans for a committee meeting. There also is a new face-to-face, late-cycle meeting that is intended to focus on information-sharing and planning for both the AdComm and the remainder of the review. Under the new review model, the committee meeting would take place in the ninth month for standard reviews, coming shortly after the late-cycle meeting, according to slides presented by Office of New Drugs Director John Jenkins at Elsevier Business Intelligence’s recent FDA/CMS Summit.

Jenkins said FDA is developing parameters for how the new late-cycle meetings will be managed. He said agency staff are concerned that sponsors will use these sessions as a means for inundating the review division with new data or appeals ([A#14121210007]).

The increased level of communication provided under PDUFA V should mean there will be fewer instances in which a sponsor pulls an application just weeks or days before a scheduled advisory committee meeting after having seen, for the first time, a negative FDA evaluation of the submission.

Prevision Policy said the new review program should make the advisory committee process more likely to be a positive event for a sponsor. Meeting with FDA behind closed doors before a public panel review takes place “should help sponsors winnow down some of the issues for discussion and prepare its best possible case to persuade the committee to vote ‘yes,’” the analysts said.

However, the new program will be of no benefit for sponsors seeking supplemental indications for previously approved drugs. Given FDA’s predilection for taking such supplemental applications before its advisory committees in 2012, it’s hard to see how that trend will be reversed by PDUFA V.

Additional reporting contributed by Cathy Dombrowski (c.dombrowski@elsevier.com)

FDA Advisory Committee Meeting Days: 2012 Vs. 2011
This chart is based on the actual number of days that committees met, according to data from FDA’s website. Some meeting days involved review of multiple drugs or issues and multiple panels.
Committee	2012 Meeting Days	2011 Meeting Days
Anesthetic/Analgesic	2	1
Anti-Infective	7	3
Antiviral	2	4
Arthritis	4	1
Cardio-Renal	3	2
Dermatologic/Ophthalmic	2	2
Drug Safety/Risk Management	2	6
Endocrinologic/Metabolic	8	3
Gastrointestinal	3	5
Medical Imaging	0	0
Nonprescription	2	2
Oncologic¹	8	7
Peripheral/CNS	1	4
Pharmaceutical Science/Clinical Pharmacology	3	3
Psychopharmacologic	0	1
Pulmonary-Allergy	1	2
Reproductive Health	2	3
Vaccines (CBER)	5	5
¹ Includes meetings of ODAC’s Pediatric Subcommittee

In With The Old? 2013 To Mark Rebirth Of CDER’s Pharmacy Compounding, Medical Imaging AdComms

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