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The benefits of proper regulatory intelligence are vast, especially at a time where speed-to-market is increasingly important. Successfully implemented regulatory intelligence can shorten time from filing to approval, increase the likelihood of marketing approval and help identify new opportunities in drug development. It can also help pharmaceutical organizations plan ahead, aiding in better prediction of regulatory review times and helping to proactively avoid potential compliance pitfalls.
What follows is what we hope will be a helpful contribution to your regulatory intelligence efforts: a brief discussion of some of the most impactful regulatory initiatives from the past year and how they play into current trends in pharmaceutical manufacturing.
PAVING THE WAY FOR PERSONALIZED MEDS
The personalized medicines market — treatments tailored to the individual patient — is growing rapidly, with revenue predictions as high as $5,208.68 billion by 2022.1 Regulatory agencies play a large role in shaping the infrastructure that enables developments in personalized medicine.
On Aug. 18, 2017, the President signed into law the Food and Drug Administration Reauthorization Act (FDARA). This new law includes the reauthorization of the Prescription Drug User Fee Act (PDUFA), intended to provide the FDA with the necessary resources to maintain a predictable and efficient review process for human drug and biologic products.
Aside from the more visible changes to the fee structure and fees, PDUFA VI also aims to do more to integrate patient perspectives into the development and regulatory review of new medicines. Launched as a new initiative in 2012, as part of PDUFA V, patient-focused drug development (PFDD) incorporates the patient’s voice into the development and review process. The FDA has committed to hold 24 disease area-specific PFDD meetings with individual patients and patient groups over the course of PDUFA VI.
PDUFA VI has the potential to strengthen the FDA’s ability to advance the science of patient input with actions, such as placing dedicated experts into review divisions to engage with patients, patient advocates and sponsors during drug development.
21st Century Cures Act
The 21st Century Cures Act (though technically signed into law in December 2016 – a little early for our 2017 recap) is intended to provide the FDA with tools aimed at modernizing regulatory programs. In July 2017, the FDA announced a detailed work plan for the steps the agency is taking to implement different aspects of Cures, which included elements that further the goals of the personalized medicines initiative, including:
• The Center for Biologics Evaluation and Research (CBER) implementing the Regenerative Medicine Advanced Therapy (RMAT) designation, enabling the FDA to facilitate an efficient development program for, and expedite review of, new regenerative advanced therapies.
• CDER, working with CBER, outlining a plan for the development of patient-focused drug development guidances.
“PDUFA VI and the Cures Act work hand in hand to bring the patient into the drug development process and ensure that drug development is actually working to the benefit of patient outcomes,” notes Lawrence Liberti, VP executive director for the Center for Innovation in Regulatory Science (CIRS). CIRS, a non-profit subsidiary of Clarivate Analytics, brings together regulators, pharma manufacturers and health technologies assessment (HTA) agencies for the purpose of advancing regulatory and HTA policies and processes used to facilitate access to medicines.
The past year saw significant progress in the ongoing quest for global alignment of regulatory expectations. Harmonizing regulations across the world would greatly reduce the complexity of the drug development process, ultimately bringing new drugs to market faster.
A key organization when it comes to global alignment is the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). ICH’s mission is to achieve greater worldwide harmonization in the production of medicines by developing guidelines via a process of scientific consensus between global regulatory agencies and industry experts.
“ICH’s aligned guidances allow pharma companies and agencies to have greater clarity surrounding regulatory expectations,” says Liberti. “In the last year, we’ve seen an increase in the number of participants that are formally recognizing ICH as an important way forward. Having alignment across growing markets will bring further clarity and predictability to the regulatory and development processes.”
Notable new members approved over the past year include regulatory agencies from Brazil (ANVISA), Korea (MFDS) and China (CFDA), while regulatory agencies from Cuba (CECMED) and South Africa (MCC) were added as observers.
As part of the ICH process, draft guidelines are transmitted to the regulatory authorities of the ICH regions for internal and external consultation. In 2017, the U.S. FDA released several draft guidances of ICH harmonized guidelines in various stages of the ICH process, including revised ICH S5 Guidelines, an addendum to E9(R1) “Statistical Principles for Clinical Trials” and a Q&A on Q11 “Development and Manufacture of Drug Substances.”
“ICH really sets a good level playing field, and I think adherence to ICH will be a key factor in promoting global alignment,” says Liberti.
The Pharmaceutical Inspection Co-operation Scheme (PIC/S) aims to harmonize inspection procedures worldwide by developing common GMP standards and providing training opportunities to inspectors. In 2017, the organization published a revised GMP guide, as well as unveiled a new strategic plan with a strong emphasis on training and better communication with heads of regulatory agencies.
In his contribution to the 2017 CPhI Annual Report,2 Bikash Chatterjee, president and chief science officer, Pharmatech Associates, points to regulatory disparity as the greatest hurdle to broad adoption of standards (such as ICH guidances), but says “that hurdle is rapidly disappearing as a result of the success of the PIC/S.”
And participation is growing. In September 2017, the PIC/S Committee invited Iran’s IFDA, Turkey’s TMMDA and Mexico’s COFEPRIS to join, effective January 2018 – bringing the total to 52 participating authorities.
Earlier in the year, PIC/S became an ICH Observer, which allows the co-op to attend ICH assembly meetings and to participate in other ICH activities. Collaboration between the two groups serves to strengthen the role both organizations play in the quest for a global pharma marketplace with shared regulatory compliance.
Global regulatory agencies continue to stress the need for ongoing improvements in product quality and are taking action by developing regulatory approaches that support continuous improvement in quality processes.
Submission of quality metrics data
In an effort to encourage the industry to implement state-of-the-art quality management systems, the U.S. FDA is in the process of initiating a quality metrics reporting program. Through this program, the Agency intends to use quality data submitted by the industry to help develop compliance and inspection policies and improve the Agency’s ability to predict drug shortages.
While the revised draft guidance for “Submission of Quality Metrics Data” was published by the FDA in late November 2016, plans are in the works for a voluntary rollout of the program starting in January 2018, with the intention of making the program mandatory in the future. The past year, however, has brought much resistance surrounding this new quality metrics program — even after the agency’s revisions, the industry still has viable concerns about the program.
In March 2017 several trade/technical organizations, led by the Association for Accessible Medicines, submitted commentary on the revised guidance, requesting further dialogue between the agency and industry before the FDA proceeds with its proposed metrics collection efforts. The letter stated that “such a program would require substantial resources, present significant operational challenges and complexities, and draw resources and management attention away from other programs that drive continual quality improvement.”
Additionally, points out Siegfried Schmitt, principal consultant, PAREXEL, the metrics collection program is still a proposal that remains isolated to the U.S. FDA. “So far no other regulatory agency has stated that they would be interested in establishing a similar concept in their jurisdiction. With an isolated concept, there is little likelihood of widespread enthusiasm within the industry to participate in the trial,” says Schmitt.
In September 2017, the FDA issued final guidance on “Advancement of Emerging Technology Applications for Pharmaceutical Innovation and Modernization,” providing recommendations to companies interested in the Agency’s Emerging Technology program.
While the guidance seeks to advance the use of emerging manufacturing technologies, such as continuous manufacturing or 3D printing, improved product quality is the true endgame. According to the guidance, not only should emerging technology be novel to the pharma industry, but it should “have the potential to modernize the pharmaceutical manufacturing body of knowledge related to product quality.”
Modern-day drug innovation requires adopting modern-day manufacturing approaches, and this guidance is an attempt by the FDA to break down some of the traditional barriers to enable a safer, more efficient drug manufacturing environment.
2017 brought significant political change – the effects of which still remain somewhat of a wild card when it comes to regulatory impact.
On March 29, 2017, the United Kingdom notified the European Council of its intention to withdraw from the European Union by March 2019. For pharma manufacturers, this move raises concerns about the European Medicines Agency, especially for companies that want to continue marketing drugs in the European Economic Area after the UK withdraws from the EU. Brexit presents challenges in several areas, notably regulatory procedures, quality testing, supply chain management and intellectual property.
In November 2017, associations representing the European and British life science industry published a letter urging Brexit negotiators on both sides to agree to a transition period that will enable continued EU-UK partnership on the regulation and supply of medicines.
Also in November, the EMA announced that it will relocate to Amsterdam, the Netherlands. EMA has developed and made public a business continuity plan to ensure operational continuity while the Agency prepares for its relocation and the UK’s withdrawal from the EU. The EMA published additional practical guidance to help pharmaceutical companies make all necessary changes to their marketing authorizations by the end of March 2019.
Early in his presidency, Trump lashed out against the FDA, calling its approval process “slow and burdensome,” while vowing to deregulate the drug industry. The crux of Trump’s message was that reducing regulatory standards would lead to more treatments reaching the market and lower drug prices – a message that was met with concerns over drug safety.
Trump’s first major FDA-related action came in the form of nominating Dr. Scott Gottlieb as the Agency’s 23rd Commissioner. Sworn in in May 2017, Gottlieb echoed Trump’s desire to overhaul the FDA, striving to reduce the red tape that he has often said hampers pharmaceutical innovation. Pharma critics initially voiced concern over Gottlieb, who had served on the boards of several major pharma companies and had strong ties to Wall Street. While it’s almost too early to form an opinion, so far, Gottlieb has seemingly found a way to work within the FDA’s system while still aggressively pushing new agency actions and policies — in particular those aimed at lowering drug prices. Under Gottlieb, that Agency has prioritized access to cheaper, generic medicines, including posting a list of brand-name drugs that lack generic competition, and fast-tracking approvals of associated generics.
In November, Trump nominated Alex Azar II, a former top Eli Lilly executive, to be the next Secretary of the Department of Health and Human Services (HHS), promising that Azar will be “a star for better health care and lower drug prices.” If confirmed, Azar will succeed Tom Price, who resigned after news broke that he spent close to $1 million on air travel in his first seven months. As HHS secretary, Azar would oversee numerous agencies including the FDA and the Centers for Medicare and Medicaid Services.
The nomination is controversial, however, considering Azar spent five years serving as president of the U.S. arm of Eli Lilly at a time when the drugmaker was highly criticized for dramatic price increases. Azar had his first confirmation hearing before the Senate Health, Education, Labor and Pensions committee on November 29th. In the hearing, Azar attributed high drug prices in part to patent abuses that stall market access to more affordable generic drugs. “This is the most important job I will ever have in my lifetime, and my commitment is to the American people, not to an industry,” Azar assured.
A LOT HAPPENS IN A YEAR
While the aforementioned regulatory actions stand out among the hundreds of guidances published in 2017 by regulatory agencies around the world, by no means is this a comprehensive list.
The past year brought with it important regulatory inroads in personalized medicines, global harmonization and quality. While political change in 2017 has left open questions for the year ahead, regulatory progress on the whole was encouraging.
1) Personalized Medicine Market Trends in Personal Care Products by 2022. Crystal Market Research (Nov 2017).
2) Chatterjee, Bikash. An Argument for Change – The Promise of the Next Decade. CPhI Annual Industry Report 2017. UBM (Oct 2017).