Editor's note: Part I of the 2018 Top 10 appeared in BioWorld's Dec. 27 issue.

While biopharma's impact was felt on the world stage, certain global events also dictated the industry's course, as indicated in the second half of our Top 10 list.

6. Biomarkers marched on, with Vitrakvi win and new regulatory guidance

Efforts to further embrace and promote the use of evidence-based biomarkers made substantial strides in 2018, both on the regulatory and research fronts. Among the most visible wins was the FDA approval for Vitrakvi (larotrectinib, Bayer AG and Loxo Oncology Inc.) to treat a biomarker-defined population of patients with a variety of solid tumors rather than those whose tumors originated in a specific location in the body. The approval reflected "advances in the use of biomarkers to guide drug development and the more targeted delivery of medicine," said FDA Commissioner Scott Gottlieb. "We now have the ability to make sure that the right patients get the right treatment at the right time." (See BioWorld, Dec. 19, 2018.)

New regulatory advice also helped advance the field. In early December, the agency published a draft of guidance on the type of evidentiary framework industry should use for biomarker qualification. The document outlines the sort of evidence the regulator is looking for to overcome what it identified as a "lack of a clear, predictable, and specific regulatory framework for the evidence sufficient to support regulatory decision-making using biomarkers," which it said has hampered the application of biomarkers in drug development to date.

Biomarkers also became an increasingly important aspect of research unfolding around the world. On the academic front, mouse experiments and human biomarker studies further strengthened the apparent connection between dementia and the cardiovascular system. Meanwhile, research on lipids established new biomarkers for atrial fibrillation and heart failure. Separately, encouraged by advances in cancer, industry R&D teams at companies such as Denali Therapeutics Inc. and Neurotrope Inc. deepened their examination of genetics and biomarkers as they seek new paths of attack on a range of neurodegenerative disorders, including Alzheimer's disease. (See BioWorld, Sept. 12, 2018, Oct. 19, 2018, and Nov. 7, 2018.)

The year also brought further credibility for biomarkers as a guide for the best use of already-approved therapies. Working with academic researchers, Roche Holding AG subsidiary Genentech Inc. found that an elevated tumor mutational burden in the blood is predictive of efficacy for its checkpoint inhibitor, Tecentriq (atezolizumab). Researchers in New Zealand found a biomarker that may be help illuminate those melanoma patients most likely to be resistant to PD-1/PD-L1-targeting immunotherapies. (See BioWorld, July 11, 2018, and Aug. 22, 2018.)

Despite the many advancements, the news was not universally encouraging. For example, during a lively session on treating chronic liver failure at the European Association for the Study of the Liver in April, scientists said that in the field of liver diseases, clinicians don't agree on the best biomarkers to predict patient outcomes, let alone the role that new biomarkers might play in facilitating patient selection for clinical trials. Similarly, in cancer, tumors with a high mutational burden, such as lung tumors, have sometimes made it harder to identify actionable driver mutations. (See BioWorld, April 12, 2018, and April 23, 2018.)

Nonetheless, with scientific and regulatory discussions driving toward the identification and validation of biomarkers in multiple indications, there can be little doubt that the role for these important signposts and targets will only continue to grow.

7. CRISPR – patents, that is – and other intellectual property matters held court

In a much-watched case, the U.S. Court of Appeals for the Federal Circuit ruled that the Massachusetts Institute of Technology Broad Institute's CRISPR/Cas9 patent claims don't interfere with those of the University of California (UC). (See BioWorld, Sept. 11, 2018.)

The precedential decision affirmed the Patent Trial and Appeals Board's (PTAB) 2017 determination that a person skilled in the art would have had no reasonable expectation of success in applying the CRISPR/Cas9 system in eukaryotic cells, given the differences between eukaryotic and prokaryotic systems. Thus, the Broad patents, which are limited to eukaryotic cells, don't interfere with UC's claims, which do not refer to a particular cell type or environment, the court said.

In handing down its decision, the appellate court pointed out that it was not ruling on the patentability of the claims. Since its opinion was limited to whether the two sets of claims are patentably distinct, there is room for further challenges, as well as an appeal.

The decision put the U.S. at odds with the EU. In January, the European Patent Office revoked a Broad Institute patent, EP 2771468 B1, on the basis that it lacked priority over novel art. The Broad Institute immediately appealed the decision, saying the patent was overturned on a technicality based on the omission of a co-inventor. (See BioWorld, Jan. 19, 2018.)

Another U.S. patent issue that made headlines this year was sovereign immunity. After making it clear that issues of sovereign immunity are to be decided by the courts and not PTAB, the Federal Circuit ruled in Saint Regis Mohawk Tribe v. Mylan Pharmaceuticals Inc. that tribal sovereign immunity cannot be asserted in inter partes reviews (IPRs). The decision also opened the door to future challenges of state sovereign immunity, which state universities have used to avoid IPRs of their patents. (See BioWorld, March 30, 2018, and July 24, 2018.)

In other patent news, shortly after IPRs withstood a constitutional challenge in the U.S. Supreme Court, the Patent and Trademark Office proposed to lessen their bite by having PTAB follow the same claim construction standard the courts use. In the past, PTAB used a broader reading that opened claims to more prior art and earned the board the reputation of a patent killer. (See BioWorld, April 25, 2018, and May 9, 2018.)

And finally, it was the end of an era as the last of Roche Holding AG's Cabilly patents expired this month. The expiration released a who's who list of the biopharma industry – both innovators and biosimilar sponsors – from licensing deals for the patents that have been foundational to monoclonal antibody development for the past 35 years. (See BioWorld, Nov. 30, 2018.)

It also was the beginning of a new era as the world's biggest blockbuster to date, Abbvie Inc.'s Humira (adalimumab), faced biosimilar competition this year in Europe for the first time. With U.S. patents extending for several more years, Humira biosimilars aren't expected to launch in the U.S. until 2023, in accordance with licensing agreements a handful of companies have signed with Abbvie.

8. Opioid woes deepened as regulators, health officials sought to reverse trends

Sadly, the raging opioid epidemic – third position on last year's list – gained a spot on the Top 10 roster this time around, as well. A barometer of regulators' caution arrived in June, when shares of Pain Therapeutics Inc. plunged more than 70 percent after a joint meeting of the FDA's Anesthetic and Analgesic Drug Products Advisory Committee and Drug Safety and Risk Management Advisory Committee voted 14-3 against recommending approval of Remoxy ER, the abuse-deterrent, extended-release, oral formulation of opioid drug oxycodone.

In August, the Austin, Texas-based company chalked up yet another complete response letter from the agency, not unexpected by analysts, though CEO Remi Barber called "bizarre" the gatekeepers' decision that benefits did not outweigh the risks of using Remoxy ER – "especially during a time of staggering human and economic toll created by opioid abuse and addiction." The NDA sought approval of Remoxy ER for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. (See BioWorld, June 28, 2018.)

As opioid addiction was recognized as the leading cause of unintentional death in the U.S., outpacing the number of deaths due to shootings and vehicle accidents combined, the feds acted last year to change how drugs in the class are prescribed, widen prevention programs and improve emergency treatments as well as long-term treatments. President Donald Trump also created the President's Commission on Combating Drug Addiction and the Opioid Crisis. (See BioWorld, Oct. 27, 2017.)

But opioid abuse persisted into 2018, at the end of which a meta-analysis in the Journal of the American Medical Association, examining 96 randomized clinical trials and 26,169 patients with chronic noncancer pain, found that "the use of opioids compared with placebo was associated with significantly less pain (−0.69 cm on a 10-cm scale) and significantly improved physical functioning (2.04 of 100 points), but the magnitude of the association was small," and the drug class "was significantly associated with increased risk of vomiting."

In November, the CDC released new statistics showing that the age-adjusted rate of drug overdose deaths involving synthetic opioids other than methadone (drugs such as fentanyl, fentanyl analogues and tramadol) increased by 45 percent between 2016 and 2017, from 6.2 to nine per 100,000. Fentanyl-related deaths just about doubled each year from 2013 through 2016, and drug overdoses along with suicides increased enough most recently to slightly lower the U.S. population's overall life expectancy.

9. Brexit drama took center stage in Europe

After a year of Brexit tumult – and now with fewer than 100 days to go before waving goodbye – the U.K. ended 2018 in political stalemate, with no majority in parliament for the withdrawal agreement, or for the other option currently on the table, of leaving with no deal. As Steve Bates, chief executive of the Bioindustry Association, put it in his monthly Brexit webinar last week, while all possibilities are open, the crystal ball needed to divine the future has melted.

Facing stasis, Health Minister Matthew Hancock has triggered contingency plans to ensure maintenance of drug supplies in the event of a no-deal, crash-out exit, telling the BBC that he is now the biggest buyer of fridges in the world. The boast was intended to show the government's Medicines Supply Contingency Planning Programme would prevent any shortages. But Hancock also dismayed the industry by extending the six weeks of possible delays at customs in the event of no deal – for which it was asked to prepare in August – to a possible six months.

That was before the crisis was deepened by Prime Minister Theresa May, who realizing she could not get approval for the withdrawal agreement, pulled the vote due to take place on Dec. 11. The volte face prompted a vote of no confidence in her leadership by members of parliament (MPs) in her own party. May won, and so cannot be challenged again for 12 months.

Parliament is now promised its say on the withdrawal agreement on Jan. 14. May is presiding over a minority government, in a parliament where most MPs favor remaining in the EU. Given 117 MPs in her party voted against her in the confidence vote, with 200 for, she is unlikely to get the 319 votes needed for approval.

The key sticking point is the land border between the U.K. and the EU in Ireland. In response to May's supplications, the EU maintained its position that there must be a legal backstop to prevent a hard border – with customs and immigration controls – between the Republic of Ireland and Northern Ireland if the U.K. and EU cannot negotiate a future trade deal. Such a trade deal would be negotiated during the transition period from March 2019 to December 2020, which will be triggered if the withdrawal agreement is approved. The industry is in favor of the outlines of that future relationship, as set out in the political declaration accompanying the withdrawal agreement. For now, however, those are intentions, not policies.

Routes around the impasse in parliament – a 'managed' no deal, a trade deal with the EU like that of Norway or Canada, a general election and a second referendum – have all been proposed. But, for now, none could secure a majority. Since the U.K. parliament clearly has to reach a majority on how the U.K. leaves the EU, there will be more maneuvering in the lead-up to the Jan. 14 vote. But with the clock ticking down, uncertainty continues to rule.

Following an edict from the EMA to prepare for the U.K. to become a third country, the pharma industry has in many senses already had a de facto no-deal Brexit. Marketing authorizations and batch testing facilities have been moved to mainland Europe and are unlikely to be brought back, even if there is a deal. But there remain many things agreed in principle that are up in the air in the absence of a deal. Those include the status of EU27 employees in the U.K. and vice versa; access to European Investment Fund venture capital; participation in EU research projects; what role, if any, the U.K. Medicines and Healthcare products Agency plays in EMA regulation in the future; the status of clinical data generated in U.K. trials. And, and, and.

The EMA itself is full steam ahead with its relocation from London to Amsterdam, where it will arrive enfeebled, with 25 percent of its staff confirmed as choosing not to move. The agency said it will gradually resume activities that were suspended and reduced to cope with the move from July 2019. But the first half of the year will see a further reduction of its work, during the final phase of its physical relocation.

The EU, too, has published contingency plans designed to prevent damage to EU27 member states if there is a no-deal Brexit, but there is no mention of medicines or health.

Embroiled in the political crisis as they are, Bates said U.K. politicians have very little understanding of the practicalities facing the industry. "They wrongly think there is more flexibility than there is," he said, pointing in particular at Hancock's change in no-deal contingency planning from six weeks to six months. It will be difficult to address that with so little time to go. "If delays at the border are longer than previously discussed that makes it harder for the sector," Bates said. "We're under no illusion this will be easy or smooth."

Nor is it right for the government to assume everyone does what they are being asked. Wholesale pharmacists already are reporting increased drug prices and agitating to be released from National Health Service contractual obligations to supply at any price. There also are concerns that drugs stockpiled in the U.K. will be exported if the pound falls further in value against the euro.

Meanwhile, as part of the contingency preparations, the government is planning emergency powers requiring pharmacists to substitute at the point of dispensing if a prescribed drug is not available. All of which leaves Bates to ponder, "How far are we going from a standard medicines market to a planned economy in our sector?"

His crystal ball may have melted, but after 2.5 years of intensive lobbying to get a Brexit deal that recognizes the needs of biotech, Bates ended 2018 predicting the March 2019 deadline will be extended.

"Procrastination has been the leitmotif of leadership, so therefore, there will be a fudge, leading to an extension," said Bates. That would open the way for more talks with the EU, a general election, or another referendum. "It's not deal, no deal, or no Brexit; it's deal, no deal, fudge, or no Brexit," he said. "Anything can happen and probably will."

10. Trade issues escalated beyond a war of words

It should come as no surprise that threats, tariffs and trade treaties round out the Top 10 on BioWorld's 2018 list. After all, President Donald Trump campaigned on his art of the deal and promised to "make America great again" by renegotiating free trade agreements (FTAs) that he claimed put the U.S. at a disadvantage.

Some of those negotiations went smoothly, resulting in revised agreements aimed at better balancing trade. For instance, Trump and South Korean President Moon Jae-in signed a revised FTA in September that both leaders said would expand trade between the two countries. The changes made to the 2012 Korea-U.S. agreement include a commitment from South Korea to amend its premium pricing policy for global innovative drugs and to ensure nondiscriminatory and fair treatment for U.S. biopharma exports.

The signing of that agreement came as new U.S. tariffs kicked in on $200 billion worth of Chinese goods, including biotech materials and medical devices. More tariffs were added as the trade war between the U.S. and China escalated for several months. Heating the rhetoric on the U.S. side were claims that China's Made in China 2025 initiative was aimed at replacing foreign technology with Chinese technology in the China market through any means possible so as to ready Chinese companies for dominating international markets. The "any means possible" came with accusations of China-authorized hacking and theft of U.S. trade secrets. (See BioWorld, Jan. 24, 2018, April 5, 2018, and April 10, 2018.)

Concerns about such threats from foreign nationals spread to U.S.-funded medical research. When prompted by lawmakers at an August Senate hearing, NIH Director Francis Collins disclosed a new investigation into thefts of federally funded research as he answered questions about the increasing risks to the security of biomedical research and the steps the NIH was taking to deal with those threats. (See BioWorld, Aug. 24, 2018.)

While Collins didn't discuss details about the investigation at the time, he said intellectual property stemming from NIH-supported research and the integrity of the agency's peer-review process has been under constant threat of risk, and the magnitude of the risks was increasing. He outlined several steps the agency was taking to address those risks without closing the door to foreign researchers.

Some of the findings of the investigation – including peer review violations, undisclosed foreign financial conflicts and undisclosed conflicts of commitment – were disclosed at a meeting of the NIH's Advisory Committee to the Director a few weeks ago. A few countries were implicated, but the report focused on the involvement of the Chinese Talent Program, which has recruited thousands of top tier researchers with access to intellectual property. Most of the recruits are involved in research funded by U.S. agencies.

On a more positive note, Canada, Mexico and the U.S. negotiated an update to the 25-year-old North America Free Trade Agreement. The negotiations were rocky at first, with the Canadian delegates walking away from the table until it became clear that Mexico and the U.S. were finalizing a pact without them. (See BioWorld, Aug. 29, 2018.)

Although the agreement, which still must be ratified, strengthens intellectual property rights, its biologic data protection provision has pleased few in the biopharma sector. The agreement sets the protection term at 10 years. That's two shy of the U.S.'s 12-year period, which brand companies were pushing for, and it's two years longer than Canada's and double Mexico's current standard, which doesn't sit well with the makers of generic drugs. The deal also expands the scope of products eligible for the 10 years of data protection.

The U.S. Trade Representative lauded the new agreement, saying it includes the most comprehensive enforcement provisions of any FTA and it would be the first to require civil remedies, criminal remedies, a prohibition on impeding licensing of trade secrets, protections for trade secrets during the litigation process and penalties for government officials who wrongfully disclose trade secrets.

And no biopharma 2018 newsmaker list would be complete without ... drug pricing

Prescription drug prices have become such a perennial, overarching concern that they merit a mention of their own outside the Top 10 list. In 2018, U.S. lawmakers missed few opportunities to raise the issue, and many of them made drug prices central to their re-election campaigns.

Throughout the year, congressional hearings on health care issues were filled with rhetoric about who's to blame for high drug prices and potential ways to force prices down. Most of the ideas have been heard before – reimportation, direct Medicare negotiation, increased competition, crackdowns on brand shenanigans, etc.

Drug prices were a key issue when Alex Azar was being confirmed as secretary for Health and Human Services in January. Many lawmakers thought that, given his biopharma career, he would be too cozy with industry to do much to rein in drug prices. (See BioWorld, Jan. 10, 2018.)

The rhetoric increased in May when Trump unveiled his blueprint to lower the cost of drugs. He touted his plan as "the most sweeping action in history to lower the price of prescription drugs for the American people" and vowed to get rid of the middlemen in the drug supply chain and to make other countries pay their fair share for drug development. Critics wryly noted the positive response of the biopharma industry and Wall Street. (See BioWorld, May 14, 2018.)

Drug companies didn't deliver the massive price cuts the president promised, but some of them did scale back on their semi-annual increases. And following a private conversation with the president, Pfizer Inc. curtailed the midyear price hikes it had previously announced. (See BioWorld, July 13, 2018.)

While Congress talked, the administration looked for ways it could put pressure on drug prices and increase generic/biosimilar competition. Azar, FDA Commissioner Scott Gottlieb and Centers of Medicare & Medicaid Services (CMS) Administrator Seema Verma rolled out several new policies to tackle the issue. For instance, the FDA created a list to shame brand drug companies that refuse to provide the necessary samples for generic and biosimilar development. It also prioritized the review of generic applications to increase competition. (See BioWorld, May 18, 2018.)

CMS proposed changes to Medicare coverage of Part B drugs and the protected classes of Part D drugs to force more competitive pricing. It reduced its reimbursement of Part B drugs purchased through the 340B discount program and, after several delays and a lawsuit filed by the American Hospital Association, recently announced that it would begin implementing a final rule in January that calculates ceiling prices for the 340B Drug Pricing Program and sets civil money penalties for drug companies that overcharge safety net health care providers for covered outpatient drugs.

CMS also banned the gag clauses payers placed on pharmacies to keep them from informing Medicare beneficiaries of cheaper alternatives for paying for their prescriptions. And it proposed requiring drug companies to include the list price of prescription drugs in their direct-to-consumer advertising. After CMS banned the gag clauses, Congress passed legislation to prevent health insurance issuers and group health plans, as well as Medicare and other government plans, from imposing the gag clauses on pharmacists. (See BioWorld, Sept. 26, 2018.)

As the year wrapped up, Azar continued to push for value-based drug pricing and a switch from the current rebate system that shrouds drug prices in a dense fog of mystery to fixed discounts.

Although the U.S. has the dubious distinction of having the highest drug prices in the world, the cost of life-saving drugs continues to be a problem in other countries. For example, the U.K.'s National Institute for Health and Care Excellence continued to balk at the price of promising new cancer drugs, such as CAR T therapies like Gilead Sciences Inc.'s Yescarta (axicabtagene ciloleucel), forcing companies to negotiate a more cost-effective price to get into the U.K. market.

And just a few weeks ago, a government program in China aimed at lowering generic drug prices plunged the stock of Chinese drug companies into their worst slump in 10 years. (See BioWorld, Dec. 13, 2018.)

BioWorld staffers Michael Fitzhugh, Nuala Moran, Randy Osborne, Karen Pihl-Carey, Marie Powers, Mari Serebrov, Cormac Sheridan and Peter Winter contributed to this report.