Biopharma Policy Actions - Pharma Intelligence/media/informa-shop-window/... · the...

Biopharma Policy Actions

2 / March 2020 © Informa UK Ltd 2020 (Unauthorized photocopying prohibited.)

Executive SummarySponsors have been asked to switch to teleconferences with FDA staff as the agency prepares for more of its employees to work from home.

The US Food and Drug Administration has implemented a full complement of coronavirus containment measures, including travel and meeting restrictions, that might endanger user fee goals and by extension product approvals.

Not only has all non-essential travel been cancelled for the next several weeks, including non-mission-critical inspections, but all Center for Drug Evaluation and Research-organized “external meetings, conferences and workshops” will be postponed through April, CDER Director Janet Woodcock said in a memo to staff.

The postponement appears to include advisory committee meetings, which could result in user fee goal dates being delayed or missed. FDA officials did not confirm whether those meetings also will be postponed or respond to questions about user fee goal delays.

Woodcock wrote in the memo, released 10 March, that staff are encouraged “to hold meetings with external stakeholders through teleconference when possible” to minimize work disruptions.

“We need to maintain continuity of operations and accomplish as much of our work as possible,” she said. The agency had earlier this week cancelled some public meetings, including the Nonprescription Drugs Advisory Committee, as the coronavirus outbreak forced events all over the world – from medical conferences

to music concerts – to be postponed. (Also see “As Coronavirus Tightens Its Grip, US FDA Cancels Some Meetings Due To ‘Extenuating Circumstances’” - Pink Sheet, 9 Mar, 2020.)

The FDA already had two drug-related advisory committee scheduled before the end of April:

• GlaxoSmithKline PLC’s Trelegy Ellipta (fluticasone furoate/umeclidinium/vilanterol inhalation powder) is scheduled to go before the Pulmonary-Allergy Drugs Advisory Committee on April 21 to discuss adding a reduction of all-cause mortality in patients with chronic obstructive pulmonary disease claim to the label. (Also see “Keeping Track: US FDA, Industry Roar Into Fourth Quarter With Bevy Of Regulatory Announcements” - Pink Sheet, 5 Oct, 2019.)

• Eli Lilly & Co.’s Avid Radiopharmaceuticals Inc. also is due to appear before the Medical Imaging Drugs Advisory Committee on 23 April for its radioactive diagnostic agent flortaucipir F18 intravenous injection, which is proposed for positron emission tomography imaging of the brain to estimate density and distribution of aggregated tau neurofibrillary tangles of Alzheimer’s disease. (Also see “Alzheimer’s Biomarker Development Hampered By ‘Limited’ Commercial Incentives” - Pink Sheet, 9 Mar, 2020.)

Both meetings remained on the FDA’s advisory committee calendar as of 10 March with no notes about postponement.

A third advisory committee, for Intercept Pharmaceuticals Inc.’s obeticholic acid (OCA) proposed indication in non-alcoholic steatohepatitis (NASH), had been tentatively

US FDA Freezes Inspections And Outside Meetings. Will Review Goal Dates Stay Put?


set for 22 April, according the firm, but was never publicly announced by the FDA. (Also see “Intercept’s NASH Drug Delayed By April Advisory Committee” - Pink Sheet, 16 Dec, 2019.) The coronavirus restrictions may mean the meeting will be delayed.

Whether any advisory committee postponements will lead to review delays is an open question. The agency isn’t required to bring applications to a committee before deciding on a product, and fewer panels have been convened in recent years. (Also see “US FDA’s Breakneck Approval Pace Clashes With Advisory Committee Mandate” - Pink Sheet, 9 Jan, 2020.)

So when the FDA does hold an advisory committee, it’s because the agency feels it really needs to – usually because it’s genuinely on the horns of a scientific dilemma or it feels the need to publicly air data about a product before making a potentially controversial decision.

Without an outside panel, the agency would have only it own judgement to rely on before making a decision on approval – but that’s what product reviews ultimately come down to anyway.

Flexibility On Pre-Approval InspectionsAnother critical element of application review, the pre-approval manufacturing inspection, could also be impacted by FDA’s coronavirus containment measures.

FDA Chief Operating Officer Jim Sigg also said in a memo to staff that all official agency travel has been cancelled through April, except when mission critical and COVID-19 response-related. Agency officials will assess whether to lift the restriction for future months on an ongoing basis, Sigg wrote.

Domestic travel will only be approved for mission-critical activities, he said.

In addition, foreign inspections scheduled in March and April that are not determined to be mission critical have been postponed, Sigg wrote.

A pre-approval inspection could be deemed mission critical, of course, but the agency could also make a risk-based determination on whether a preapproval inspection was even necessary based on the nature of the manufacturing process and how recently the plant had been inspected.

A growing manufacturing trend toward efficiency bodes well for the FDA’s ability to rely on previous inspections when it cannot schedule a timely preapproval inspection. Production has gravitating toward larger facilities that produce a wider array of products, increasing the chances that the agency would be able to rely on a recent inspection to assess GMP compliance.

(This trend has also been a problem for approvals, with manufacturers sometimes receiving complete response letters from the FDA because of other inspections identifying problems in completely unrelated plant operations. But now it could be a boon.)

Technology, Collaboration Allow Oversight Of Foreign PlantsWoodcock said the agency plans to use “technology and established agreements with foreign counterparts to minimize disruptions to the drug supply chain and applications under review.”

Commissioner Stephen Hahn said in a statement that among the reasons for the decision to delay inspections was “our ability to maintain oversight over international manufacturers and imported products using alternative tools and methods.” Those include using the mutual recognition agreement to obtain information from other governments, reviewing compliance histories, and requesting records in advance or in lieu of on-site


visits.

“We will be vigilant and monitor the situation very closely and will try to mitigate potential impacts from this outbreak in lockstep with the whole of the federal government,” Hahn said. “We stand ready to resume foreign inspections as soon as feasible.”

Mutual recognition allows the FDA to rely on facility information gathered by several European nations. (Also see “Mutual Recognition’s Next Evolution May Be Sharing Info On India And China Inspections” - Pink Sheet, 11 Jul, 2019.)

The decision to suspend foreign inspections represents an expansion of earlier scheduling changes caused by the outbreak of coronavirus. When the virus first emerged in China, the agency postponed about 100 scheduled inspections there in February and March as a precaution. (Also see “The Quality Lowdown: On Redeploying Inspectors, API Suppliers Thanks To Coronavirus” - Pink Sheet, 25 Feb, 2020.)

FDA Asking In-Person Meetings Be Converted To TeleconferencesFDA officials also seems to be encouraging at least some sponsors to change scheduled in-person meetings to teleconferences to limit the potential for exposure to coronavirus.

Multiple sources who work with industry told the Pink Sheet that CDER is contacting sponsors with in-person meetings scheduled in the near term and asking to convert them to teleconferences.

If an in-person meeting cannot be avoided, agency officials are mandating that only principals may attend with two to three FDA staff. The remainder

must dial in to the session.

The agency did not confirm whether meetings are in fact being converted to teleconferences.Preparing For Mass TeleworkSigg also wrote in the memo that the agency is preparing for a substantial increase in telework by FDA employees.

“We are evaluating and actively testing our IT systems to make certain that we are prepared for greater than usual telework should the need arise,” he wrote.

Sigg added that agency employees who may telework should take laptops and work assignments home daily in case events arise that could impact their ability to work at the agency. Those without telework agreements also were encouraged to put them in place.

Several companies and other groups already have advised employees to telework, both as a precaution and because of coronavirus exposure. Biogen Inc. also gave the telework directive to employees at several offices after cases were traced to an internal company meeting. (Also see “In A Volatile Time, Pharma Reassures Business Remains Steady” - Scrip, 9 Mar, 2020.)

The industry’s primary trade association, the Pharmaceutical Research and Manufacturers of America, decide to close its Washington D.C. headquarters for the rest of the week and conduct a deep cleaning of the facility after a visitor who attended a meeting there tested positive for coronavirus. PhRMA said in a statement that the person was last in its office 5 March and that others who were at the meeting have been asked to self-quarantine.


Executive SummaryThe UK’s Medicines and Healthcare products Regulatory Agency says that any increase in clinical trial protocol deviations in relation to coronavirus outbreak will not constitute a serious breach.

The UK medicines regulator says it expects to see a rise in protocol-related deviations in ongoing clinical trials as a result of disruptions caused by the COVID-19 outbreak, which the World Health Organization declared a pandemic on 11 March.

The Medicines and Healthcare products Regulatory Agency has clarified that any increase in protocol deviations in relation to coronavirus “will not constitute a serious breach” and should not be reported to the agency, unless there is a risk to patients. Companies should ensure that all deviations are well documented to enable appropriate evaluation for the trial, the agency said.

The MHRA said it was aware of challenges arising in relation to coronavirus and the effect this was having on the conduct of clinical trials. As a result of the outbreak, patients may be advised to stay away from hospitals and GP sites, or they may be reluctant to travel or they may be advised to self-isolate, which may result in them being unable to undertake required clinical trial activities. In addition, organizations managing and sponsoring clinical trials may be experiencing a higher proportion of staff working from home during this period.

“This has led to reports of protocol and standard operating procedure deviations due to missed

visits, or changes in processes… Wet-ink signatures have also been difficult to obtain in a timely manner if staff are not in the office, and this can delay some clinical trial processes,” the MHRA said.

To manage the situation, the agency suggests that companies should consider:

• Reassessing certain oversight duties in hospital settings, such as monitoring and quality assurance activities, and introduce alternative proportionate mechanisms of oversight, such as phone calls, video calls etc, to ensure ongoing subject safety and well-being. The MHRA recommends a brief risk assessment and documentation of the impact of this, with consideration of prioritization of critical activities such as safety reporting.

• Introducing remote monitoring while ensuring this does not place an extra burden on trial sites. The trial subjects should consent to sharing of their personal information outside the trial site.

• Adopting alternative methods of demonstrating approvals (in place of wet-ink signatures) such as email confirmation. The MHRA said its inspectors would take a pragmatic approach to this, but companies should consider a standard operation procedure (SOP) deviation to cover this in the interim.

Prospective Protocol Waivers UnacceptableDisruptions by COVID-19 can also impact recruitment to ongoing trials. In this context, the MHRA clarified that it remains strictly opposed to “prospective protocol waivers,” which are memos that sponsors sometime issue allowing a trial site to enrol a patient who does not meet all inclusion

UK MHRA: COVID-19 To Spark Rise In Clinical Trial-Related Deviations


or exclusion criteria, or to give a site pre-approval to deviate from protocol-defined visit windows.

The UK regulator told companies that prospective protocol waivers are unacceptable as “we would not expect you to bypass the eligibility process due to difficulties in assessing subjects and carrying out tests.” Similarly, if the safety of a trial subject is at risk because they cannot complete key evaluations or adhere to critical mitigation steps, then consideration to discontinuing that

subject must be discussed.

The MHRA noted that the sponsor and investigator have the authority to use “urgent safety measures” or even temporarily halt a trial, or halt recruitment, where necessary. Companies must ensure that any temporary halt, including for logistical reasons such as trial team unavailability, needs to be submitted as a substantial amendment to ensure the MHRA has complete oversight.


Executive SummarySome transitional arrangements may help Indian drug firms process export obligations already underway prior to recent government restrictions designed to safeguard domestic supplies against the backdrop of supply chain stress due to the coronavirus outbreak. But will the Indian government tweak the restrictions to balance home demands and exports?

Amid apprehension in some international markets over the recent export restrictions imposed by India on a basket of active pharmaceutical ingredients (APIs) and formulations, there appears to be ongoing dialog between industry and the government to strike a balance to safeguard both domestic medicines security and commercial opportunities.

On 3 March, India notified a list of 26 APIs and formulations, including paracetamol, tinidazole and metronidazole, for which exports had been restricted with immediate effect in view of supply chain uncertainties caused by the coronavirus outbreak that started in China. The move was ostensibly to ensure that the home market does not face any major disruptions amid the evolving situation. (Also see “India Curbs Exports Amid Coronavirus” - Generics Bulletin, 4 Mar, 2020.))

But sections of the Indian pharma industry have been quick to point out the risks of such extensive curbs – competitors may try and exploit any market vacuum and India should not cede its position of strength while also prioritizing steady domestic supplies.

The Indian industry is hoping that things improve on the API supply front from China, given that the country accounts for an estimated 65-70% of total

imports of APIs and intermediates into India. But there are also fears in some sections that if Indian firms renege on supply deals (e.g. institutional supplies) as a result of the export curbs, it could have longer-term implications and competitors will be quick to move in.

Some FlexibilityIndustry executives told Pink Sheet that the government has been generally receptive to suggestions about permitting exports of some of the products listed in the notification, in cases where these are covered in prior tender allotments or if the API supplies are “especially quoted for exports” or involve “short expiry” APIs.

“The government has been open to listening to industry and the overall purpose is that both domestic demand and basic export obligations are met,” one senior industry executive indicated.

Local media reports also suggest that industry lobby groups like the Indian Drug Manufacturers’ Association have sought that the 3 March notification be retracted in view of the current surplus available to meet international demand and on the assurance that all stocks would be made available for domestic needs should shortages emerge.

There have also been efforts to emphasize to various international organizations, including the World Health Organization (WHO), that the curbs on Indian exports are only being done to “balance” domestic supplies and export commitments, the executive added.

Last week, US Food and Drug Administration Commissioner Stephen Hahn told US lawmakers at a hearing of the Senate Health, Education, Labor and Pensions Committee that the agency was evaluating India’s export restrictions to

India Export Restrictions: Balancing Tweaks In Store?


determine whether these would affect the US drug supply.

India is a key supplier of generic drugs to the US, with some estimates suggesting that one in every three pills consumed in the country is produced by an Indian manufacturer. (Also see “Coronavirus May Boost Policy Efforts To Enhance US Drug, Medical Supply Production” - Pink Sheet, 3 Mar, 2020.))

Long Term SolutionIt’s not immediately clear if the Indian government will fine-tune or tweak the 3 March notification imposing export curbs, though Mansukh Mandaviya, minister of state for the ministry of shipping and the ministry of chemical and fertilizers, was reported as referring to the move as “short-term restrictions.”

Some industry experts, however, said that while restricting exports may be one way of tackling shortages, it is basically another “myopic action” unlikely to solve the problem at hand. A long-term solution, they underscored, lies in a return to API manufacturing with a focus on local supply (not for exports).

“While API manufacturing facilities exist in India they are relegated to complex APIs. That needs to be broadened out. This is a long-term solution, so seeking East European or Central Asian bulk manufacturers to fill in the gap is essential for immediate succor,” Salil Kallianpur, a former executive vice-president at GlaxoSmithKline India who now runs a digital health consultancy, told Pink Sheet.

But he noted that the industry is sandwiched between price caps, margin rationalization and increasing input costs, adding that a “bit of flexibility there might also encourage companies to tread down that [API] path with more surety.”

Satish Reddy, president of the Indian Pharmaceutical Alliance and chairman of major Indian firm Dr. Reddy’s Laboratories Ltd., emphasized in a recent interview with Scrip that the government and domestic industry need to work in alliance and quickly to regain some of the Indian sector’s past dominance in the API space and to avoid a public health scare. (Also see “IPA Chief Reddy: Coronavirus API Supply Impact A ‘Big Wake Up Call’ For India” - Scrip, 6 Mar, 2020.)

The head of another domestic firm told Pink Sheet that industry has, for several decades, been “preaching” why India needs to be self-sufficient in APIs and that the government has to partner these efforts in earnest . “The government should review what happened in the past and act soon. Some of us have lived through the tough times in the past and know the serious risks,” the executive added.

Transitional ArrangementsMeanwhile, the Pharmaceuticals Export Promotion Council of India (Pharmexcil), set up by the ministry of commerce and industry, has clarified some specifics around the 3 March notification imposing export curbs on certain bulk drugs and formulations.

Pharmexcil drew attention to the transitional arrangements available under India’s Foreign Trade policy (2015-20) when the government effects any restriction or policy change for items otherwise exported or imported freely. Under these arrangements, the importability/exportability of a particular item is governed by the policy as on the date of import/export; the bill of lading and shipping bill are the key documents for deciding the date of import and export respectively.

Under these transitional norms, exports will essentially be permitted for goods awaiting shipment at ports, by air etc. and where


shipping bills have been filed and bills of lading acknowledging receipt of cargo for shipment (or similarly airway bills) have been issued prior to the notice effecting restrictions. However, imports through “high sea sales” are not be covered under this facility.

The transitional arrangements also specify that import/export on or after the date of such regulation/restriction will be permitted for importers/exporters who have a commitment through an Irrevocable Commercial Letter of Credit (ICLC) prior to the date of the restrictions. However, this is to be limited to the “balance

quantity, value and period available in the ICLC.”

To operationalize the ICLC, applicants will need to register the letter with the jurisdictional regional authority against the computerized receipt within 15 days of imposition of any such restriction/regulation.

Pharmexcil said that it is also engaging with India’s Directorate General of Foreign Trade to relax the restrictions on the “shipments lying at ports and also for the supplies meant for other countries,” though the specifics of this were not immediately clear.

For full coverage on Coronavirus from Pink Sheet, please click here

https://pink.pharmaintelligence.informa.com/search#?q=coronavirus%20or%20COVID-19

Biopharma Policy Actions - Pharma Intelligence/media/informa-shop-window/... · the...

Documents

Transcript of Biopharma Policy Actions - Pharma Intelligence/media/informa-shop-window/... · the...