With the Food and Drug Administration’s Safety and Innovation Act (FDASIA), the Agency’s added a fourth expedited approval pathway – “Fast Track, Breakthrough Therapy, Accelerated Approval and Priority Review, Expediting Availability of New Drugs for Patients with Serious Conditions,” which expedites development and review for drugs intended to treat serious conditions, and provides significant improvement over existing therapies. As of April 2014, FDA received 165 requests for breakthrough status and has granted 42 such designations.
Most Breakthroughs are cancer drugs, although the latest designation (March 20) was earned by Pfizer for a meningococcal vaccine.
Breakthrough was in part a reaction to criticisms that FDA’s approval times were inordinately long, even though this notion was debunked in a June 14, 2012, New England Journal of Medicine article that compared FDA approval times with those of overseas regulators.
The experience of Catalyst Pharmaceutical Partners (Coral Gables, Fla.) is representative. Catalyst’s Firdapse therapy, for treating Lambert Eaton Myasthenic Syndrome (LEMS), received Breakthrough status in 2013. LEMS is a debilitating neuromuscular disease for which no safe treatment exists. Lack of competition, the seriousness of the disorder and encouraging efficacy signals played decidedly in favor of Firdapse.
BREAKTHROUGH STATUS CHALLENGES
While highly desirable, Breakthrough status challenges sponsors to keep product development on track, says Steve Miller, Ph.D., chief scientific officer at Catalyst. “Since the Agency is committing critical resources to expedited reviews, it expects companies to follow through with equal dedication, positioning these programs on the front burner.”
Nothing in FDA guidances or in FDASIA requires the Agency to investigate whether sponsors are capable of attaining development milestones expeditiously. One could imagine some level of due diligence based on a sponsor’s resources and previous compliance issues, but that is only conjecture.
Expedited review helps patients and the sponsor, which enjoys a longer exclusivity period for products. It also improves FDA’s image for facilitating timely approval of critical medicines. One thing it does not do is substantially help sponsors for follow-on indications. “There are no regulatory shortcuts,” Miller emphasizes. “Basic safety studies are of course indication-neutral. Other than that, submissions for second or third indications proceed normally.”
Orphan Drug status is another work-around that continues to be profitable. Sponsors receive a decent return on investment in the short term, says Susan Bain, DRSc, professor of practice, clinical, regulatory and quality at the Keck Graduate Institute of Applied Life Sciences (Claremont, Calif.). “Afterward, they can initiate clinical trials for a second indication and hope for off-label business as well. The idea is to get the drug out faster, with less data, and a lower clinical burden, all while benefiting from the drug’s market presence.”
Closely paralleling FDASIA’s supply chain directives are the EMA’s 2013 Falsified Medicines Act, which tightens requirements and control over drug product ingredients, including excipients, and similar laws in other jurisdictions, particularly in emerging markets. (Editor’s note: For a full account of FDASIA’s supply chain initiatives and additional commentary, see “Taming The Supply Chain Monster.”
Given the global nature of pharmaceutical industry sourcing, for both materials and services, FDASIA was long overdue. Luba Skibo, executive director at NSF International, an independent global standards-writing, training and education firm predicts rapid and significant growth of auditing activities and inspection readiness, including a rise in paper audits and site visits. “Five years ago, supply chain security was a vision, a plan, an initiative. Today it is a reality,” Skibo says. “It will still be here five years from now, hopefully with clear directions for implementation.”
GLOBAL REACH
FDASIA grants FDA the unprecedented authority to regulate foreign suppliers of raw ingredients and active pharmaceutical ingredients that make their way to U.S. markets, whether the eventual manufacturer domiciles stateside or overseas. While no geographic region of the supply chain is invulnerable, FDA will likely direct most of its oversight to countries with less-than-stellar reputations for following accepted business practices.
If the Agency believed, however, that its headaches would begin and end with supply chain regulation, last year’s scandal involving a GlaxoSmithKline (GSK) business unit in China dispelled that notion. The scandal, which involved bribery to promote off-label prescriptions, has deeper relevance in light of the company’s record-setting $3 billion fine in 2012 for engaging in similar behavior in the United States. And just this past April, GSK was found to be employing similar tactics in Iraq.
While FDA has no direct authority over foreign bribery cases, these incidents could alert the Agency to potential domestic wrongdoing. Eventually, FDA will discover that it cannot ignore malfeasance simply because it occurs beyond its territorial jurisdiction.
On the surface, GSK’s overseas troubles suggest that developing countries are beginning to take corruption seriously. Or, conversely, these incidents unveil even deeper malfeasance.
“There is tremendous, intense new global scrutiny of marketing and promotional content, clinical data integrity, manufacturing conduct and quality assurances, which had been traditionally taken up only by the U.S, and, to a lesser degree, the U.K.,” says David Resnicoff, an attorney at Miller & Chevalier (Washington, D.C.).
So far, so good. GSK’s transgressions suggested a pattern of disregard for well-established promotional practices that quite naturally spilled across borders. But Resnicoff suggests that officials in emerging markets and companies eager to establish themselves in those markets (GSK’s China operates generated 4% of the firm’s income before the scandal) are playing a game of double-bluff.
Luba Skibo, executive director at NSF International, identifies two trends that will affect FDA-manufacturer relations for years to come. The first is implementation of the new ICH tripartite model for an effective Pharmaceutical Quality Management System (QMS), as enunciated in ICH Q8, Q9 and Q10 guidances. Based on ISO concepts, ICH Q10 outlines a unifying approach to an effective pharmaceutical quality and incorporates GMPs, ICH Q8 (pharmaceutical development), and ICH Q9 (quality risk management). The ambitious ICH Q10 is a model for a pharmaceutical quality system that spans a product’s lifecycle.
“These ideas are moving from QMS design, components identification and structure around component to the ‘how-to stage,’” Skibo says. “Over the next few years, industry will be learning how to use and apply knowledge management and quality risk management to different components of QMS. Dropping no-value-added practices and metrics will be an exciting and challenging journey toward continuous improvement.”
She adds that the industry must learn how to implement knowledge and risk enablers to harmonized, lifecycle-long QMSs, and to implement them in a way that fosters innovation, effectiveness and competitiveness while assuring patient benefits.
According to Skibo most companies have identified critical QMS components and infrastructure, and are entering what will inevitably be a trial-and-error exercise for implementing it. This will occur first at best-in-class organizations. As the buzz dies down, lessons learned at the top are expected to trickle down into the industry as a whole.
The other regulation to watch is the 2012 FDA Safety and Innovation Act (FDASIA), particularly its supply chain initiatives. “Attention to the excipients and API supply chain control expected from industry is illustrated by the FDASIA provision that ‘failure to manage the supply chain is GMP failure, and product considered adulterated,’” Skibo says. “Further reinforced by the Drug Quality and Security Act of 2013, supply chain security will be the focus of FDA and industry attention for the next 10 years.
GOVERNMENT’S OPEN HAND
“Certain emerging markets have woken up to the great sums of money they can make by forcing global companies active within their jurisdictions into paying large settlements over alleged malfeasance. GSK’s conflict with Chinese regulatory authorities was a signal event, likely to be replicated in Russia and Brazil. Executives are wondering when, if ever, it will end.”
FDASIA established regulation as an international endeavor. Robert Young, North American life sciences serialization and track and trace lead at Accenture, suggests that oversight has already expanded beyond supply chain issues. “Pharmaceutical industry regulators face unprecedented pressures in the form of increasingly stringent, globally driven health authority requirements and complex product obligations for initial filings, lifecycle management and ongoing compliance.”
These pressures have intensified the challenge to companies of maintaining authorization for a full portfolio of products 12,000 miles away from headquarters, while continuing to innovate and seek greater efficiencies at home. “Meeting these challenges strains capacity and diverts precious resources from the ultimate goal of bringing new, differentiated products to patients,” Young adds.
Regulatory agencies, moreover, must now confront product expansions into new demographics and geographies, while monitoring the flow of goods and services from these overseas markets into the United States (e.g., FDASIA’s supply chain provisions).
Young believes that current practices for managing pharmacovigilance are “unlikely to be sustainable.” Regulators’ workloads are expanding rapidly, at 10–20% a year, a result of higher regulatory expectations, tougher inspection regimes, business growth and more proactive physician/patient reporting.
INTER-AGENCY COOPERATION
Companies need to determine how the growing flow of granular data can provide value, while regulators have to make sense of it all. The solution, says Young, will be new ways to process and interpret “big data,” much of which will originate overseas. Moreover notions of patient privacy differ dramatically between the U.S./U.K. and developing markets, which will by necessity involve inter-agency cooperation, similar to that encouraged by FDASIA.
“These data concepts are new territory,” Young says. “Companies recognize that they are not data analysis experts and may not want to staff internally to support this. Hosted services will therefore evolve in this area, but even they require skills that integrate back to companies’ supply chain data to create a full end-to-end picture.”
CMC CHANGES
In keeping with the climate of continuous improvement in manufacturing operations, sponsors often file submissions to implement post-approval production changes. FDA categorizes CMC changes as major, moderate and minor. Major changes carry “substantial potential to have an adverse effect on the identity, strength, quality, purity or potency of a drug product.” Major changes require submitting a supplement, called a Prior Approval Supplement (PAS), and FDA approval before distributing products produced as a result of the change.
As expected, moderate changes carry “a moderate potential to have an adverse effect” on the product. One type of moderate change requires submission 30 days before distribution and is called a “Changes Being Effected in 30 Days” submission, by which FDA has 30 days to decide. If the Agency decides information is missing (the most common reason for denial), the subsequent corrections are identified as Changes Being Effected (CBE). Minor changes, which are expected to have little impact on the product, are handled through the Annual Report submission.
The official book on manufacturing changes is embodied in CFR 314.70(a)(1)(i), which states that “the applicant must notify FDA about each change in each condition established in an approved application…” and 314.70(a)(2): “The holder of an approved application … must assess the effects of the change before distributing a drug product made with a manufacturing change.”
The most common reasons for CMC change submissions are facility (34%), control (34%) and actual manufacturing alterations (16%). Thus, fewer than one-sixth of applications involve what a chemist or chemical engineer would call chemical process changes. Historically, the fraction of these falling into the PAS (riskiest) category has been less than 5%. Perhaps reflecting sponsors’ reliance on risk-based strategies, PAS filings rose to about 10% between 2010 and 2012. Still, significant chemical process changes represent only 1% of all post-approval submissions under the larger umbrella of “CMC changes.”
From filing data alone, it is clear that companies rarely consider significant CMC changes — even when economically justified. But submission data tells only part of the story. Companies appear to be taking more liberties with assessments of CMC change riskiness.
Geoffrey Wu, Ph.D., from FDA’s Office of Generic Drugs, has spoken and written on post-approval CMC changes. In a 2014 study, Wu noted that the total number of supplements for generic drugs, CBE 30 submissions, and CBEs, remained approximately equal between 2005 and 2012. These figures are approximately 3600 for total submissions, 2700 for CBE 30s, and 575 for CBEs. At the same time, PAS submissions rose six-fold, from fewer than 100 in 2005 to approximately 600 in 2012. The rise in PAS applications most likely reflect industry’s embrace of risk management, albeit more in facility, control and packaging than in chemical processing.
At the same time, FDA has subjected medium-risk submissions to greater scrutiny. FDA upgraded 55 CBE/CBE 30 applications, 1.6%, to PAS in 2005. By 2012, 150 such applications, 4%, were upgraded into the higher risk category.
Determining causal factors for the 150% increase in upgrades is not easy, but the consequences are obvious for an industry that lives and dies by market exposure. According to guidances, getting bumped into a higher risk category delays the point at which companies may distribute post-change drug products — a fact that Wu acknowledges.
He disagrees, however, that risk upgrades are a natural result of any new thinking regarding risk-based compliance. “Risk is solely decided by the nature of the proposed change,” he explains. “Any reasonable applicant should conduct risk assessment on proposed changes prior to regulatory submission and implementation. FDA’s risk-based approach is to further assure product quality and safety.”
The most common reasons for upgrading a risk category are lack of scientific or product information, failure to cite appropriate guidances, insufficient investigation of out-of-specification product, lack of supporting information for CMC changes, and paradoxically, too much unnecessary information.
How to explain, then, given the resources devoted to regulatory compliance, the rise in misunderstanding risk levels for relatively straightforward CMC changes? Wu has no explanation. “Industry folks may give you further insights to this question,” he says.
BECAUSE THEY CAN
Companies purposely underestimate risk in regulatory filings because they can, says Susan Bain. “They’re looking to shortcut testing time and the amount of data they need to supply to justify the CMC change.” She says the practice is “huge” at top companies. “It’s a matter of resource allocation,” she says. Companies obviously benefit from expending less time, money and product than they normally would to achieve a risky CMC change.
Some companies (particularly startups) are so time-crunched that they may institute changes based solely on a letter-to-file — basically putting a letter into a file that states they observed no risk to products from process changes. Then they play catch-up when regulators ask about the letter. Bain believes that companies consciously weigh the cost of rejection against that of completing studies. “It sometimes comes down to how long it takes to validate a new process before getting caught,” she says. Some tactics resemble grade school strategies. “They will submit a CB30 without the validation data, hoping to have completed the studies before regulators reach that part of the submission. When confronted, they say, ‘Oh yeah, here it is.’”
The submissions that FDA cites are often those that fail to complete validation before time is up due to unsuccessful studies. For these firms the clock starts all over again, often with product sales put on hold, and inventories recalled. “It’s horrible publicity and very expensive, particularly for temperature-sensitive products or those with short shelf-lives,” Bain says.
Incomplete data is a problem that goes beyond post-approval CMC changes, according to Bain. “Forty percent of NDAs are sent back because of incomplete data.” Again, the problem lies mostly with sponsors who believe they will be able to play catch up between submission and FDA action. “The market is so competitive, and with generics knocking at the door, companies are taking more risks to streamline the approval process in any way they can.” She stresses that this activity is limited to regulatory submission risk, not patient safety. “Sponsors are not cutting corners with quality.”
Bain recalls one firm, seeking approval for a new filling line lacked critical validation data. “They didn’t get the work done in time and had to start over. In the long run that didn’t save them any time.” Such companies, she adds, often develop bad reputations with regulators who feel they are wasting Agency time.
Regardless of how the uptick in original and re-designated PAS submissions originates, the risk-based approach to development and regulatory review are here to stay. “Most companies understand and accept this reality,” says Luba Skibo.
COMPLEX QUESTION
FDA has already adopted risk assessment for inspections, as sponsors implement similar practices for auditing suppliers and service providers. How risk plays into post-approval CMC changes is a complex question.
In its landmark 2004 cGMP revision guidance, FDA enunciated its cooperative, risk-based vision to exploit advances in quality management and to allocate limited regulatory resources more effectively. CMC regulatory review, according to the guidance, “should be based on an understanding of product risk and how best to manage this risk.” CDER’s follow up guidance, CMC Post-approval Manufacturing Changes to Be Documented in Annual Reports, extended the risk-based approach to CMC review, and recognized that many post-approval CMC supplements posed low risk.
This extensive list included relaxation of blend uniformity testing, changes in coatings and mixing times for immediate-release drugs, and alterations in filtration parameters excluding pore size. Subsequent guidances outlined how, and to what extent, companies needed to document low-risk changes through the Annual Report. Without going into details, it was obvious that FDA’s goal was to streamline submissions while simultaneously sparing the Agency’s need to review vast volumes of irrelevant data. “While not directly linked to cGMPs for the 21st Century, this certainly seems like an application of risk management,” Skibo says.
