key: cord-0787913-prwma8ut
authors: CARPENTER, M.I.C.H.E.L.L.E.A.; NOVACK, G.A.R.Y.D.
title: FDA Review Times for New Drugs in Ophthalmology
date: 2020-08-11
journal: Ocul Surf
DOI: 10.1016/j.jtos.2020.08.003
sha: bba0bfe3419e5d82a4254a3e1d50189b1da4c988
doc_id: 787913
cord_uid: prwma8ut

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The key U.S. law that gave the FDA regulatory authority to make benefit/risk decisions on NDAs and BLAs was the Kefauver-Harris act of 1962. In the years that followed, the time interval from NDA/BLA submission until FDA approval ranged from 88 days to 10 years for ophthalmology products. In the late 20 th century, the U.S. Congress, FDA and firms came up with a solution to consistently provide more rapid reviews. This compromise resulted in enactment of the Prescription Drug User Fee Act (PDUFA) in 1992, which is reauthorized every 5 years. Under PDUFA, firms pay a fee to support additional reviewers at the FDA. FDA in return "promises" to review most of the NDAs/BLAs in 10 months and some designated as priority review, in 6 months. With PUDFA V or new molecular entities (NMEs), an additional 60 days was added to the PDUFA date (for a total of 12 months and 8 months, respectively).

The fee was initially about US$250,000. Under PDUFA VI it is now approximately US$2.9 million. Fee exemptions and waivers are granted for small businesses or for applications for orphan diseases. Applications have PDUFA target completion dates and their timelines for review are contained within the FDA benchmarks. Also note that this is the time to review. It does not guarantee approval, and that review may be a negative decision, or a decision requiring additional effort by the firm.

Approximately 20 years ago, one of us (G.D.N.) reviewed ophthalmic NDAs. The review time for NDAs in the early 1990's had a wide range, with a mean of 44 months. 1 The review time came down to 11 months in 1996 after implementation of PDUFA. the application involves a new molecular entity (NME), if a major amendment was submitted during the review, and whether the NDA received a priority review. They noted the special programs of accelerated approval, breakthrough therapy designation, and fast track designation. 3 Of the divisions, the two Oncology Divisions had the most NDAs (67). DTOP had 26 NDAs.

We estimate that at least 75% of the 26 NDAs reviewed in DTOP were ophthalmology. Of the 26 NDAs submitted to DTOP, approximately 85% were standard reviews and 15% were priority reviews. Of the 26 NDAs, approximately 25% were NMEs (Table 1 ). The average review time for DTOP was approximately 275 days, which was as rapid or faster than most divisions, with the exception of hematology and oncology, with average review times of approximately 250 days. The median was similar to the mean. However, as one might expect, there was a wide range on the minimum and maximum review time. The GAO concluded that FDA met the PDUFA program goals.

J o u r n a l P r e -p r o o f pipeline oct_2020_v1.docx/1 august 2020/page 4 As many readers know, in the U.S., the "practice of medicine" allows physicians to prescribe an approved for a given patient for any indication as they see fit (21 U.S. Code § 396). That said, there are de facto limitations on this practice -for example, the medication may not be covered by insurance. Also, there may not be adequate information to practice evidence-based medicine. Thus, in addition to the information on initial NDAs above, we also reviewed the U.S. law and practice for secondary or subsequent applications for these additional indications in ophthalmology. These supplements are covered in the PDUFA framework. There are target timelines for review of supplements containing clinical data. The target timeline for priority supplements is 90% within 6 months and for standard supplements is 90% within 10 months. and target timelines for supplements, which remain unchanged, are funded through program fees for marketed products. 4 In order to assess review times for supplemental submissions for ophthalmic drugs, we used our internal list of approved ophthalmic drugs, selecting initial NDA/BLA approvals from 2010 to 2020 (approximately 60 drugs). We manually reviewed FDA CDER's database, "Drugs@FDA", evaluating the type of review (Priority or Standard), type of supplement (indication or dosage form change requiring clinical data), and FDA timeline for review. This list was substantiated through review of independent articles and literature. We excluded from this analysis the many label changes that reflect manufacturing, packaging, safety and pediatric supplements. Thus, we aimed to select only those applications which reflected additional efficacy indications. From the FDA website and review of Summary Basis of Approvals, we developed a list of efficacy supplements for ophthalmic products containing the type of review (Priority or Standard), type of supplement (indication or dosage form change requiring clinical data), and FDA timeline for review. This list was substantiated through review of independent articles and literature.

In our review, we found four products with 11 efficacy supplements in the ten-year review period. As shown in Table 2 , two products were in retina and two products were in inflammation. With one exception, the review intervals were either 6 or 10 months. The one exception, a product requiring nearly 4 years between submission and approval, reflects FDA's requests for additional data, and the Sponsor's time to obtain and resubmit that data. There are several limitations to this analysis. First, it was manual, and thus subject to our identifying ophthalmic drugs, and further selecting which among the supplemental approvals met the criteria for an efficacy analysis. For example, one product had 114 supplemental applications in the 11 years since initial approval. Second, unfortunately, it is not possible from publicly available information to ascertain the designation of all supplements (priority versus standard), which would enable relative comparison to the PDUFA user fee goals. Third, the input for this analysis is only approved drugs, and approved supplemental indications. We are not able to see those drugs either not approved, or currently in development. Finally, we use only U.S. data, which is more generally available that other countries.

That said, there are two clear conclusions: There are relatively few second indications approved (11 indications for 4 products), and in general, FDA meets similar review times for supplemental ophthalmic as for initial ophthalmic indications. Further, one can deduce that higher quality submissions result in more rapid review timelines, this thinking does not take into account that the overall timeline to market may have actually been reduced by a conscious decision on the part of the Sponsor to file as soon as possible. In our experience, we suggest frequent communication with the FDA to assure alignment with regulatory expectations by the Sponsor.

The Tufts Center for Drug Development has conducted more extensive evaluations of drug development using confidential data over the entire pharmaceutical and biomedical industry. In general, our conclusions and interpretations are similar. [5] [6] [7] [8] J o u r n a l P r e -p r o o f pipeline oct_2020_v1.docx/1 august 2020/page 7 Thus, in conclusion, for both initial and subsequent approvals in ophthalmology, review intervals for quality submissions for both initial and supplemental indications appear to be consistent with PDUFA guidelines. This is useful in Sponsors' planning for subsequent marketing and availability to patients and physicians.

Ophthalmic Products Related to the Ocular Surface • Oculis announced that based upon a meeting with the U.S. FDA, they are pursuing Phase 3 clinical trials for OCS-01 (topical dexamethasone) for the treatment of inflammation and pain following cataract surgery as well as diabetic macular edema (DME, July 2020).

• Osmotica Pharmaceuticals received FDA approval for its Upneeq™ (oxymetazoline hydrochloride ophthalmic solution, 0.1%, RVL-1201) for the treatment of acquired blepharoptosis, or ptosis (July 2020).

• Roche received approval from Japan's Ministry of Health, Labour and Welfare for its Enspryng® (satralizumab) to treat adults and children with neuromyelitis optica spectrum disorder (June 2020). The firm also announced results of its Phase 3 study of the Port Delivery System with ranibizumab for the treatment of neovascular age-related macular degeneration (July 2020).

• Tarsus Pharmaceuticals announced results of two Phase 2 studies of the effects of its topical TP-03 in the treatment of demodex blepharitis (June 2020).

• Viela Bio received FDA approval for its Uplizna® (inebilizumab), a CD19-directed cytolytic antibody given intravenously, for the treatment of neuromyelitis optica spectrum disorder (June 2020).

• Adverum reported interim data on the first 3 cohorts of patients, and dosed a patient in the 4 th cohort of the phase 1 OPTIC trial of intravitreal ADVM-022, a vector capsid for aflibercept (May 2020).

• Applied Genetic Technologies Corporation (AGTC) announced expansion of its ongoing Phase 1 /2 clinical study of its gene therapy treatment of X-linked retinitis pigmentosa (XLRP) caused by mutations in the RPGR gene (July 2020).

• Gensight announced clinical data from an early stage clinical trial, PIONEER, of a combination of its gene therapy (GS030, channel rhodopsin) and light stimulation for the treatment of retinitis pigmentosa (July 2020).

• jCyte announced results from its Phase 2b clinical trial of its cell therapy for patients with retinitis pigmentosa (July 2020).

• Ocugen received orphan designation status for its gene therapy (OCU400) for the treatment of RHO mutation-associated retinal degenerative disease (July 2020).

• Alcon received U.S. FDA approval for a switch of their olopatadine hydrochloride ophthalmic solution 0.7% from prescription to over-the-counter (July 2020). • Ocuphire is merging with Rexahn. The combined company will focus on the advancement of its pipeline of ophthalmic drug candidates (June 2020).

• Santen negotiated an ex-U.S. licensing deal for jCyte's Jcell, a human retinal progenitor cell therapy initially aimed at treating retinitis pigmentosa (May 2020).

• Clinical trial researchers are considering the impact of the COVID-19 pandemic, including less consistent follow-up visits, reduced movement, or poorer mental or physical health, on statistical analyses. For example, reduced sample size may decrease the power of studies to detect a treatment effect. Also, it may be challenging to select an unbiased method to adjust for missing data.. 9 • CURE ID, a collaboration between the FDA and the National Center for Advancing Translational Sciences (NCATS), part of NIH, is a repository that captures clinical outcomes when drugs are used for new conditions, in new populations, in new doses or in new combinations. CURE ID is being used as a repository for re-purposing existing drugs for novel indications, including management of COVID-19 (June 2020).

• H. Holden Thorpe Ph.D., editor of Science, proposed that education alone will not counter the problem of science denial in the population. Rather, he proposes that "…The only way to win this fight is to harness the same sophisticated tools in the name of science that are being used to tear science down" -meaning to use social media to promote science." 10 • U.S. Food and Drug Administration (FDA):

o Estimated that 80% of active pharmaceutical ingredients and 40% of drug products (the finished medication as dispensed to the patient) were manufactured overseas, mainly in China and India. With international trade threatened by the global pandemic, there is a growing concern in the U.S. over foreign pharmaceutical manufacturing.. 11 o Issued a draft guidance outlining the agency's current thinking on the development of drugs containing cannabis or cannabis-derived compounds (July 2020 to treat certain hospitalized patients with COVID-19. The agency determined that the legal criteria for issuing an EUA are no longer met (June 2020). • Legislative bills are pending in several states to allow physicians to dispense prescription medications, currently not allowed (June 2020). 12 • Pharmaceutical company sales representatives, who typically meet with physicians faceto-face, are having to change their communication to alternate methods during the COVID-19 pandemic. As well, the role of these representatives post pandemic may change (May 2020). 13 • The ACTIV (Accelerating COVID-19 Therapeutic Interventions and Vaccines) Review times are calculated from initial submission until approval. These reflect FDA review time, as well as Sponsor response time in answering FDA requests for additional information.

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