Jill Wechsler is Pharmaceutical Technology's Washington Editor, jillwechsler7@gmail.com.

Jill Wechsler

	Continued public alarm over opioid-related overdoses and deaths is generating additional strategies to reduce opioid prescribing and production and to crack down on firms for inappropriate marketing of these therapies. Related FDA initiatives support the development of less addictive pain therapies and new treatments for addiction, at more affordable prices.

	At the same time, states and municipalities have brought hundreds of lawsuits against opioid manufacturers and distributors for aggressive promotion that spurred excessive prescribing of painkillers, and the Department of Justice recently said it would join efforts to recover costs for federal government opioid treatment programs. These actions have increased pressure on pharmaceutical companies to monitor and limit opioid production and distribution, and on physicians and other health professionals to modify prescribing.

	A main initiative is to reduce individual access to large quantities of pain pills through a range of actions by FDA and other federal agencies. The Drug Enforcement Agency (DEA), which regulates production and prescribing of controlled substances, is moving to curtail the manufacture of opioids where there’s evidence of illegal diversion. Attorney General Jeff Sessions 

in April 2018 that the proposed policy would add drug abuse or diversion to the list of factors that DEA uses to set quotas for opioid production (1). DEA also would be able to obtain more information from states, FDA, Medicare and Medicaid, and the Centers for Disease Control and Prevention (CDC)-in addition to data from manufacturers-in setting annual production limits for drugs such as oxycodone and fentanyl.

 that it is joining settlement talks with drug manufacturers, states, and other entities involving litigation over opioid production (2). Such action was spurred by reports of distributors delivering more than 20 million painkiller tablets to pharmacies in a small town in West Virginia, a visible sign of intended illegal diversion.

	However, it’s not clear how the new DEA rule would affect the market. Traditionally, the DEA production quota system was designed to ensure that drug manufacturers produce enough of needed medicines to avoid shortages in needed pain therapies, and quotas have been determined largely by manufacturer projections for drug sales in coming months. Whether or not the DEA can use the same process to reduce supply remains to be seen, as it may be difficult to identify a particular manufacturer related to a broader oversupply situation.

	Recent DEA moves to limit opioid manufacturing, moreover, may have contributed to ongoing reports from hospitals and clinics of serious shortages in injectible pain medicines needed for surgery and for treating cancer patients and others experiencing severe pain. The limited supplies are linked to manufacturing problems at a leading Pfizer facility producing pre-filled syringes and vials of morphine and other potent medicines. Hospitals continue to seek alternative suppliers for injectables and to use more pills and less potent analgesics where possible. Health professionals, however, fear that the need to administer unfamiliar injectables with different strengths and delivery systems may lead to dosing errors.

	Congress aims to enact legislation by summer to curtail access to opioids and to expand funding for substance-abuse treatment programs. A notable provision in bills moving through the Senate and House aims to reduce opioid use by authorizing FDA to require drug manufacturers to provide oral formulations in blister packs with limited three- or seven-day supplies. FDA also could require safe disposal packaging systems that block re-use of leftover drugs. FDA and stakeholders examined these strategies at an FDA public workshop in December 2017 on the role of packaging, storage, and disposal options in addressing opioid abuse.

	These provisions are part of the much broader 

 approved by the Senate Health, Education, Labor and Pensions (HELP) committee in April (3). The House Energy and Commerce Committee similarly has developed a comprehensive opioid package of bills that support addiction treatment, research on non-opioid pain therapies, and curbs on excessive prescribing. The legislators clarify FDA authority to remove pain therapies from the market if found less effective in limiting abuse than when initially approved, and for the agency to obtain information that can assist in detecting and seizing counterfeit and illicit drugs coming into the country.

	Congress further supports the development of new non-addictive pain therapies by directing FDA to issue guidance on designing clinical trials and on developing alternative treatments. FDA would clarify how it weighs the risks and benefits of drugs with potential to be misused or abused, while also offering expedited and breakthrough pathways to manufacturers of novel pain and addiction treatments. The National Institutes of Health similarly gains authority to provide funding more quickly for promising research proposals related to treatments for pain and addiction.

	These measures build on FDA initiatives to encourage innovation in developing treatments to limit the euphoric effects of opioids, in addition to methadone, buprenorphine, and naltrexone. FDA issued a draft guidance in April 2018 on developing new sustained-release buprenorphine products less vulnerable to misuse or abuse (4). The agency also proposes abbreviated development and testing programs for new therapies similar to already approved treatments that differ in delivery systems or formulations. In addition, FDA is revising the content of training information provided by manufacturers to prescribers under an expanded Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS), which now includes both immediate-release and extended-release opioid analgesics.

	Democrats would like legislation to impose tougher penalties on manufacturers and drug wholesalers and distributors for marketing and distribution practices calculated to expand opioid use. At Congressional hearings, Democrats loudly criticized drug companies for promoting excessive prescribing and for channeling funds to patient pain advocacy organizations to support wider use of certain therapies. Sen. Bernie Sanders proposed a bill that levies stiff fines and prison sentences on drug company executives involved in illegal opioid marketing and distribution, along with reduced exclusivity and tax credits for firms convicted of such activities. Leading opioid manufacturers earlier this year announced plans to limit or cancel promotional activities, but still may face penalties designed to help defray public outlays for costly addiction and rehab programs.

	There may be some relief ahead, as seen in reports of a sharp drop in the volume of pain medicines prescribed and dispensed to patients in 2017, according to data from 

 (5). The trend indicates that physicians are responding to advisories from CDC and FDA and other health authorities to reduce opioid prescribing overall and to limit the number of doses in those prescriptions considered necessary. FDA looks to continue the trend with further advice on clinical study design related to addiction treatments and the development of non-opioid pain therapies. The agency also aims to examine whether new formulations do support abuse deterrence, Gottlieb said in 

 before Congress on FDA’s budget plan (6). The commissioner urged payers and health plans to expand coverage for therapies to prevent overdoses and to treat addiction, as well as non-opioid pain medicines. To ensure that patients suffering from pain have access to appropriate treatment, FDA is holding a public meeting on July 9, 2018 to hear from patients and medical professionals on strategies to support prescribing guidelines and pathways for developing new pain threapies (7).

	1.  Department of Justice, “Attorney General Sessions Announces Charges in DEA Opioid Limit Rules,”

, April 17, 2018.
	2. Department of Justice, “Attorney General Sessions Delivers Remarks on the Trump Administration’s Response to the Opioid Epidemic,” 

Opioid Dependence: Developing Depot Buprenorphine Products for Treatment, Guidance for Industry, Draft Guidance

 (CDER, April 2018)
	5.  IQVIA, “IQVIA Institute for Human Data Science Study: US Prescription Opioid Volume Declined 12 Percent in 2017–Largest Drop In 25 Years,” 

President’s Fiscal Year 2019 Budget Request for FDA–House Testimony

, April 17, 2018.
	7. S. Gottlieb, MD, “Addressing Needs of Patients While Stemming the Tide of the Opioid Crisis,” 


	Vol. 42, No. 6
	June 2018
	Pages: 14–15

	When referring to this article, please cite it as J. Wechsler, "Manufacturers Under Pressure to Curb Opioid Use and Abuse," 

Articles

FDA and Congress seek to limit the production and distribution of pain medicines.

Manufacturers Under Pressure to Curb Opioid Use and Abuse

	After months of debate, Congress enacted legislation yesterday that establishes a pathway for terminally ill individuals to gain access to investigational products. Even though FDA has a well-established and effective expanded access/compassionate use program that assists very ill patients in obtaining not-yet-approved therapies from sponsors, agency critics have long demanded stronger action to remove roadblocks to experimental treatment.

	FDA commissioner Scott Gottlieb, MD, and previous agency leaders have maintained that this legislation is not needed and may expose desperate individuals to harmful or ineffective treatment. They also have concerns that the latest bill undermines FDA authority to vet and approve important new medicines based on safety and efficacy. Under pressure from the Trump administration, Gottlieb recently softened his opposition, stating that FDA can implement the new policy without harming agency operations or safeguards.

	The Right-To-Try (RTT) bill initially sponsored by Sen. Ron Johnson (R-Wis) was approved by the Senate in August 2017 in a deal to move forward must-pass legislation to renew FDA user fees. The House passed its own version of the Senate measure in March 2018, which added provisions to address patient safety and limit liability of prescribers and drug companies, as sought by patient groups and manufacturers. But the Senate failed to approve the House measure, prompting RTT advocates to press for House approval of Johnson’s original bill. The House now passed the Senate bill by a strong margin, largely along party lines, sending it to the White House for President Trump’s signature.

	RTT legislation has been promoted by the libertarian Goldwater Institute of Arizona with strong backing from the Koch brothers. While its stated goal is to provide life-saving treatment for seriously ill individuals, it also challenges the FDA approval process for biopharmaceuticals by reducing incentives for patients to participate in clinical trials and for manufacturers to finance long clinical testing programs. Almost 40 states have enacted their own right-to-try laws, but its backers have long sought federal legislation. The Goldwater Institute also is promoting state laws that permit off-label promotion by pharmaceutical companies, which has recently been successful in Arizona and Tennessee. These bills prevent states from taking action against pharmaceutical sales reps or healthcare institutions engaged in truthful promotion of off-label drug uses.

	The federal RTT law permits terminally ill patients to go directly to drug companies to request access to experimental drugs that have moved to Phase II testing, bypassing FDA’s compassionate use process, which regularly authorizes 99% of requests from patients and physicians for early access to unapproved drugs. In both the current and the new process, a biopharmaceutical company developing a new therapy can decide whether or not to provide an experimental product to an individual. Such decisions are particularly difficult for small companies that often lack sufficient supplies outside clinical trials. Sponsors have concerns that very ill patients will suffer serious adverse events that can compromise a drug development program and FDA approval of the new therapy. And industry fears liability claims from patients who fail to respond or decline under treatment.

	Friends of Cancer Research and a long list of medical research organizations and professional societies strongly objected the bill. The opponents claim it creates serious risks for patients, undermines an effective drug regulatory process, and raises false hopes for individuals seeking help. Industry organizations have been quiet on the issue but will face challenges in dealing with new requests.

Right-to-Try bill sent to White House for President’s signature after passage by Congress. 

New “Right-to-Try” Law Challenges FDA Oversight

	After months of expectations and repeated delays, President Donald Trump formally announced his strategy for making prescription medicines more affordable and accessible in the United States. Trump promised to take on the “tangled web of special interests” that drive up drug prices, noting the high amount that pharma companies spend on lobbyists to “protect the status quo” and “keep drug prices high.” He also cited supply chain middlemen for getting “very rich” under the current system and promised regulatory and legislative changes to address the status quo.

	Despite the rhetoric, Trump’s proposals stopped short of giving the government authority to negotiate Medicare drug prices or liberalizing curbs on drug imports, policies strongly opposed by pharma. The sigh of relief could be heard throughout industry and the investment community, providing a lift for industry stock prices. 

	Instead, a main initiative unveiled by Trump on May 11 was proposed to compel other industrial nations to pay more for innovative medicines, particularly Canada, Japan, and some European countries. Under the “American Patients First” 

, the administration will challenge “global freeloading” through actions that reduce price disparities and spread the burden for incentivizing new drug development between the US and other developed nations. Although it’s unclear how the Trump administration will achieve this goal, one idea is to publish a comparison of drug prices in the US and other Organization for Economic Co-operation and Development (OECD) countries to expose the differences. The President also called for the US trade representative to address this “injustice” in trade discussion with all trading partners.

	A main component of the Blueprint is to reduce Medicare and Medicaid spending on drugs, as changes in government programs can be accomplished by administrative action. Multiple policy changes aim to bring more competition to Medicare Part D plans and to revise reimbursement under Part B. But instead of authorizing the federal government to negotiate Medicare drug prices directly, as urged by Democrats and many consumer representatives, the White House aims to reduce prices and out-of-pocket costs for beneficiaries through greater transparency in Medicare list prices and rebates, limiting price increases on Part B drugs, encouraging greater generic-drug use by low-income seniors, and returning to Medicare beneficiaries those rebates negotiated by pharmacy benefit managers (PBMs) and manufacturers. One new proposal is to examine whether drugs that raise prices too often or too much can remain in the protected classes of Part D plans.

	One newer idea outlined by Health and Human Services (HHS) secretary Alex Azar is to promote drug price competition by requiring drug marketers to include pricing information in DTC broadcast ads. “If we want to have a real market for drugs, why not have them disclose their prices in the ads?” Azar queried. That, he said, would give consumers more balanced information, and companies would face “a very different set of incentives for setting their prices.” Azar wants FDA to look at whether it can require disclosure of list prices as part of “fair balance” requirements. Implementing such a program, though, raises many questions about what pricing data would be disclosed and under what authority.

	President Trump also praised FDA for promoting competition in drug markets by approving a record number of new generic drugs, as 

 by commissioner Scott Gottlieb. The White House plan further supports FDA policies for developing more complex generic dosage forms and for deterring brand firms from blocking generic-drug makers from access to innovator products needed for bioequivalence testing. Similarly, the administration supports efforts to streamline and accelerate the approval process for over-the-counter drugs to further boost market competition.

	Azar said that there would be a close look at the current drug rebating system involving pharmacy benefit managers (PBMs), manufacturers, and health plans and how rebates affect PBM compensation. And the HHS secretary wants to get rid of “gag rules” that limit how pharmacists can steer customers to less costly products, and to require doctors to disclose out-of-pocket costs for drugs they prescribe for patients.

	Meanwhile, leading Congressional Democrats offered more aggressive proposals for lowering drug prices, most requiring legislative action. The top priority is to permit Medicare to use its purchasing power to negotiate prices directly with plans and manufacturers. Democrats also want more transparent calculation of the “true cost” of drug production as a basis for pricing, and they urge an end to tactics designed to extend patent protections, such as pay-for-delay deals, patent “evergreening,” and the use of FDA Risk Evaluation and Mitigation Strategies (REMS) to block competition.

	There’s the perennial call for “safe” importation of prescription drugs from other countries and revisions to trade agreements to encourage competition and access to affordable medicines. And they propose to appoint a “price gouging” czar with authority to fine drug companies for raising prices beyond certain limits.

	Azar noted that many of the Blueprint proposals can be accomplished through executive action, but that change may take some time if new rulemaking is required. The administration seeks “fundamental structural change” to a system of “entrenched market players,” he commented in a press briefing. This announcement, he said, should launch a national dialogue with all stakeholders and with Congress.

President Donald Trump announced his strategy for making prescription medicines more affordable and accessible in the United States.

Trump Drug Pricing Plan Outlines Rule Changes Pharma Can Live With

	The use of more targeted therapies able to treat patients more effectively and efficiently is expanding as the public gains access to low-cost genetic testing, and more advanced computer systems are offering data from healthcare systems. With some 75,000 genetic tests on the market, more consumers are signing up for personal analyses, and clinicians are ordering genetic lab tests to inform treatment. Problems arise due to uncertainty over how to interpret such test results and concerns about privacy may limit data sharing. Unclear and inconsistent reimbursement policies for genomic tests, moreover, create barriers to advancing precision medicine, as does limited access to testing by certain population subgroups.

	Yet, research indicates much promise for the field, as seen in a range of studies from leading researchers and clinicians presented in the May 2018 issues of 

. Cystic fibrosis (CF) patients with a certain genetic mutation experienced measurable gains from treatment with Ivacaftor (Vertex Pharmaceuticals’ Kalydeco), according to a study conducted by the Cystic Fibrosis Foundation and other researchers. This analysis of administrative claims data showed that improved outcomes reduced hospitalization rates for patients treated with the drug from 2012–2015, with the gains correlated with strong adherence to treatment. The trends continued for use of ivacaftor to treat patients with additional CF gene mutations under indications subsequently approved by FDA. The outcomes reduced healthcare spending more broadly, further demonstrating the value of assessing real world treatment data for innovative treatments.

	Precision medicines able to rapidly demonstrate effectiveness for targeted patients also benefit from more expedited development and accelerated approval by FDA. An examination of FDA data for 2013–2017 by researchers in Australia and at Harvard Medical School found that precision medicine studies generate early signals of efficacy and reach the market more rapidly than traditional drugs. Almost half of the precision medicines in the study qualified for FDA’s breakthrough therapy designation and were approved based on fewer pivotal trials and with fewer patients in studies, who were less likely to be randomized, blinded or have placebo controls. Such gains enabled product development and review 1.7 years faster than nonprecision products.

	FDA’s Oncology Center of Excellence (OCE) is collaborating with organizations able to capture real-world data on patient treatments and outcomes in electronic health records to better assess the potential benefits or risks of treatment to patients outside conventional clinical trials. By linking clinical records to genomic data from thousands of tumor samples, the analysts sought to identify study populations able to provide generalizable evidence for precision medicine interventions. Achieving such a data infrastructure is highly complex, reported OCE Acting Associate Director Sean Khozin in a case study on linking clinical and genomic cancer data to inform precision medicine use. The analysis in 

 supports efforts to establish data standards and strategies to support data sharing in this area across multiple providers and labs.

	The development of more targeted therapies for limited patient populations, though, raise concerns about cost and access. Generic versions of targeted therapies initially did little to bring down the cost of specialty innovators products, according to a 

 study. It found that the list price of imatinib (Novartis’ Gleevec) fell only 10% following the approval of the first three generic versions, largely because physicians continued to prescribe more expensive brand therapies.  

	Payers increasingly are turning to value-based payment models in establishing reimbursement for new targeted oncology therapies and other specialty medicines. The Centers for Medicare and Medicaid Services (CMS) reported on how it is exploring methods for adjusting payments under its Oncology Care Model and other alternative payment methods.

The use of more targeted therapies is expanding as the public gains access to low-cost genetic testing, and more advanced computer systems are offering data from healthcare systems. 

Precision Medicines Speed Development and Reduce Healthcare Costs

	To better manage a growing number of applications for new drugs that treat disease in innovative ways and involve new kinds of clinical research programs, FDA officials are mapping plans to restructure the Office of New Drugs (OND) in the Center for Drug Evaluation and Research (CDER). A main goal is to “flatten the organization,” explained CDER director Janet Woodcock, with more reviewers authorized to make decisions on review findings. This shift to smaller review divisions should reduce bottlenecks in the review process, she explained at the annual meeting of the Food and Drug Law Institute (FDLI) last week in Washington, DC. An OND reorganization steering committee heads up the effort, and, she emphasized, the review program modernization effort is “proceeding according to plan.”

	Commissioner Scott Gottlieb similarly highlighted how OND modernization will help FDA adapt to important scientific changes in medicine. The overall aim, he explained in a keynote speech at the FDLI meeting, is to better align new drug development and review with new types of medicines designed to target molecular changes that initiate disease, and “not just the symptoms of illness.” This shift will require new approaches to documenting and evaluating applications, including a team-based review process that brings together staff with expertise in areas such as statistics, modeling, simulation, and advanced manufacturing to assess novel trial designs and drug development approaches.

	“We want it to be easier to innovate the way drugs are developed,” Gottlieb commented. Our professional staff members are “thought leaders in their disciplines,” he observed, “and we want to give them more time to collaborate with academic medical scientists and patients, to analyze scientific and commercial developments, and to strategically foster drug development.”

	The process for documenting reviews will be revised to highlight issues and data of greatest importance, while also reducing the sometimes redundant memos generated by multiple review processes. Woodcock noted that CDER staffers are developing a new template for documenting multiple aspects of a review, including toxicology, clinical pharmacology, and clinical review.

	A new Office of Policy in OND will play a key role in developing more consistent policies and procedures across disease areas, Woodcock added. This office will facilitate the development of more “bullet guidances” that provide short, timely advice on specific topics involved in developing certain therapies. Such guidances are faster to draft and to finalize, and CDER hopes to issue 30–40 such advisories a year.

	Gottlieb further described the OND changes at the annual meeting of the Reagan-Udall Foundation the next day, noting that he expects CDER to begin unveiling these initiatives by the end of this summer. The OND reorganization will establish more focused therapeutic divisions, he explained, such as separating the current Division of Gastroenterology and Inborn Errors Products into divisions for gastroenterology and for liver disease. He also anticipated that a common review template would reduce the multiple memos developed by each review discipline.

	Such a broad and complex reorganization of this important CDER operation, involving the formation of new review divisions and a new policy office, will take time to move through the formal federal government review process, Woodcock pointed out. Yet, she and her staff have orchestrated such restructuring efforts for generic drugs and for drug quality oversight in recent years, and she anticipates a similarly successful modernization effort for the new drug review process.

Smaller review divisions will bring experts closer to decision processes and reduce bottlenecks, FDA leaders say.

FDA Moves to Overhaul New Drug Review Process

 anniversary of the 1918 influenza pandemic that killed an estimated 50 million people is prompting public health authorities and the biomedical research community to seek new strategies to address global health threats. An immediate goal is to improve the effectiveness of seasonal flu vaccines, while advancing the development of a universal flu vaccine that can provide multi-year protection against multiple influenza strains.

 on April 27, 2018 in Boston, Bill Gates described how a lethal airborne flu virus could quickly spread around the world and kill 33 million people in six months. To avoid such a catastrophe, Gates announced the launch of a new “grand challenge” award by the Bill & Melinda Gates Foundation, along with Google co-founder Larry Page and his wife, to provide $12 million in grants to researchers discovering “game-changing” approaches for testing and developing a universal flu vaccine. He also cited the need for more effective antiviral therapies, rapid diagnostics, and advanced computer data systems to combat and prevent a pandemic.

	The prospect of American scientists taking the lead in discovering new life-saving preventives may appeal to the White House, as seen in Gates’ comments on a private talk in March he had with President Donald Trump. Gates hopes that his message on how a global pandemic threatens the United States will counter administration moves to curb foreign aid, particularly for world health programs. This effort has support from Congress, where a group of leading Senators are 

to renew and improve the federal program for combating threats from bioterrorism and pandemics.

	The National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health (NIH) continues to play a key role in developing new vaccines for multiple diseases, including a universal flu preventive as outlined in a 

. FDA commissioner Scott Gottlieb has voiced concerns about the limited effectiveness of the current seasonal flu vaccine, which speaks to the importance and challenges in developing a universal, multi-year preventive. At a Congressional hearing in March, 

 the need to shift from the traditional egg-based method product method to cellular and recombinant protein products that appear to yield a vaccine that is more effective in protecting against dangerous flu viruses. Faster seasonal vaccine production systems would allow more time to analyze data on the viral strains most vital for a new vaccine to target. Several vaccine makers are making such changes, but the shift has been slow.

	Efforts to prevent another flu pandemic also can build support for tackling multiple health threats around the world. This was highlighted at a conference this week marking the 50

 anniversary of the NIH Fogarty International Center, which analyzes data on global infections and funds the training of biomedical research scientists and clinicians to combat disease in less-developed regions [see 

https://www.fic.nih.gov/About/50th-anniversary/Documents/fogarty-international-center-nih-at-50.pdf

 ]. At the conference, Anthony Fauci, director of NIAID recounted how the imperative to halt the lethal HIV/AIDS outbreak 40 years ago drove global health initiatives and led to the development of anti-retroviral medicines that transformed AIDS from a death sentence to a manageable disease, at least in the US. Fauci noted similar recent successes in combating the Ebola outbreak and Zika due to advances in global disease surveillance systems, local capacity building, and collaborative clinical research that can help deal with future pandemics.  

	In his recent speech, Gates expressed optimism about such advances, citing a growing pipeline of broadly neutralizing antibodies with potential to protect against a pandemic virus and of more rapid diagnostics that harness genetic engineering technology. He cited public-private initiatives, such as the Coalition for Epidemic Preparedness Innovations (CEPI), which supports research on new vaccines and therapies for killer pathogens such as Lassa fever and the Middle East respiratory syndrome, MERS, and the development of rapid response platforms able to quickly produce new vaccines for a range of infectious diseases.

	To be prepared for a pandemic, Gates emphasized the need for a military-style mobilization plan with trained personnel ready to act. Such a program would include manufacturing and indemnification agreements with pharmaceutical companies to enable industry to move quickly in an emergency to produce needed treatments. “Our biopharmaceutical industry is the global leader in biomedical innovation,” Gates said, and should be instrumental in the US playing a “leadership role in creating the kind of pandemic preparedness and response system the world needs.” New vaccines, antibiotics, and rapid diagnostics will be critical in combating a flu pandemic and in addressing outbreaks of even more lethal pathogens at home and abroad.

Public health authorities and the biomedical research community are seeking new strategies to address global health threats.