India’s Drug Advisory Body Calls For Larger Study To Approve Pfizer’s Xeljanz

The New Drug Advisory Committee said the number of patients enrolled in Pfizer’s Xeljanz trials was not statistically significant to recommend marketing authorization.

MUMBAI – Pfizer Inc.’s newest blockbuster hope, the first-in-class JAK inhibitor Xeljanz (tofacitinib) approved in the U.S. last November to treat moderate to severe rheumatoid arthritis (RA), has encountered a regulatory setback in India. The newly formed New Drug Advisory Committee (NDAC), which vets drug approvals and clears clinical trials, said the number of patients enrolled in the Indian study was not statistically significant for recommending marketing authorization for the immunosuppressant.

Pfizer had generated clinical trial data on 120 Indian subjects, according to government records.

Bigger The Better

In a July 27 meeting, the Analgesics, Anesthetics and Rheumatology NDAC recommended that Pfizer conduct a trial with a statistically significant number of Indian patients. “The sites should be multi-specialty hospitals/institutes having [their] own Institutional Ethics Committees including 50% of sites being government hospitals across the country. Accordingly [clinical trial] CT protocol etc. may be submitted to the [Drug Controller General of India] DCGI for further review of the committee,” NDAC said.

Pfizer noted that its clinical trials strategy for new drugs includes a strong emphasis on meeting the requirements of local regulatory agencies.

“Xeljanz has been studied in a comprehensive, global, multi-study clinical development program that included approximately 5,000 patients across Phase II and III trials in more than 40 countries, resulting in 7,000 patient-years of exposure,” the New York-headquartered company told PharmAsia News in a statement.

While Pfizer presented global clinical trial data supporting Xeljanz for adult patients with moderate-to-severe active RA, NDAC asked for a larger number of patients to be enrolled in the Indian study. It however did not specify what number constituted a “larger number of patients,” leaving the question open for the next set of trials and making it difficult to assess how much additional time would be needed to reach final product approval.

Pfizer took the regulatory objections in a positive light, saying it supported NDAC’s goal of ensuring that medicines approved by other regulatory agencies globally are safe and effective for Indian patients.

“The company is currently evaluating the feedback from the NDAC and will explore further clarification on expected additional data. Pfizer remains confident in Xeljanz and further plans on Indian clinical trials will be decided after regulatory consultation,” Pfizer explained.

NDAC Adding To Delays

Through a March 2011 order, the Ministry of Health and Family Welfare established 12 New Drug Advisory Committees to make their assessments on broad therapy areas like analgesics, cardiovascular, vaccines, dermatology and allergies, neurology and psychiatry. The committees will assist the Drug Controller General of India to review clinical trials and approve new drugs. The committees constitute key opinion leaders drawn from government-run hospitals and medical institutions like the All India Institute of Medical Sciences in New Delhi and Mumbai-based KEM Hospital.

Established to maintain high regulatory standards in clinical trials and drug approvals, the committees were formed in response to criticism from patient groups about inefficiencies in the regulatory system. India’s highest judicial authority, the Supreme Court, also slammed the government and urged it to tighten industry controls to ensure patient safety (Also see "Faced With An Adverse Verdict, India’s Clinical Research Industry Pushes For A Quick Makeover" - Scrip, 4 Jan, 2013.).

While appreciating the formation of NDAC, executives in the clinical research space are skeptical about the role it plays in regulating drug approvals and clinical trials.

A senior industry official said each NDAC has about 10 members, but the meetings are not well attended. He said at times only three committee members decide the fate of drug approvals and may not be a “truly representative” figure.

Also, clarity is needed on what “large-scale studies” mean because definitions are not specified in clinical trial guidelines, he said (Also see "India CROs Say DCGI Trial-Approval Switch To NDAC Too Costly" - Scrip, 4 Jul, 2012.).

Recommendations for larger studies on complex or first-in-class drugs like Pfizer’s Xeljanz may mean that trial approvals or marketing authorizations may get delayed inordinately.

The exec also noted that the DCGI has been extremely slow or inactive in granting trial approvals. “How does Pfizer generate additional data when there is a near freeze situation on approvals for clinical trials?” (Also see "Sneak Preview: Clinical Trial Policies Top IP As Biggest Obstacle To Indian Innovation" - Scrip, 19 Jun, 2013.).

Pfizer’s Xeljanz is an orally delivered drug and could have a competitive edge over a number of RA injectables on the market. It was approved by U.S. FDA last November for RA patients who have not responded adequately or are intolerant to biological disease-modifying anti-rheumatic drugs. The drug, however, is sold with a boxed warning related to risks like infections, tuberculosis, lymphoma and some cancers (Also see "Pfizer’s Tofacitinib Clears FDA Without Limited Indication" - Pink Sheet, 6 Nov, 2012.).

In July, the European Medicines Agency’s Committee for Medicinal Products for Human Use decided not to recommend approval for Xeljanz, noting the risks of taking the medication did not outweigh the benefits (Also see "EMA Knocks Back Pfizer’s Xeljanz For Rheumatoid Arthritis and Otsuka’s Delamanid For TB" - Pink Sheet, 26 Jul, 2013.).