FDA is moving fast to implement the drug compounding provisions of the new Drug Quality and Security Act (DQSA), issuing new guidance to spur registration by outsourcing facilities just days after President Obama signed the new bill into law. Because FDA cannot compel compounders to opt for agency regulation, implementation will rely largely on market pressures to encourage healthcare providers to purchase compounded products only from registered facilities, explained FDA commissioner Margaret Hamburg at a press briefing Dec. 2, 2013.
The bacterial meningitis outbreak at Princeton University in recent weeks has raised questions about why there is no vaccine in the United States to prevent this deadly disease, when such a therapy is approved in Europe and Australia. The current Princeton health danger prompted the Centers for Disease Control and Prevention (CDC) to request emergency import of the vaccine, and the Food and Drug Administration approved that move, authorizing an investigational new drug application (IND) for Novartis’ Bexsero vaccine. New reports of additional meningitis B cases in California may spark further discussion about ensuring US access to protection against this dangerous infection.
The situation illustrates the complexities of vaccine development, approval and reimbursement at home and abroad. Studies to document vaccine safety usually require testing in thousands of healthy individuals, plus certain high-risk populations. There are four meningitis vaccines licensed in the US, but they protect against four other meningococcal disease strains, and not B, which has proven more difficult to attack.
Moreover, meningitis B is not that prevalent in the US, so Novartis and other vaccine makers have concentrated clinical trials for B preventives in Europe, Australia, and other regions. The resulting study data supported market approval for Bexsero in the European Union in January 2013 and more recently in Australia. More trials have been launched in Latin America and even Canada, but not in the US where Novartis did run a small, early trial on adolescents several years ago. Meningitis is most deadly in infants and very young children, and testing in those populations raises difficult risk-benefit calculations for a relatively uncommon condition.
In April 2011, the FDA advisory committee on vaccines and related biological products discussed the effectiveness of meningococcal vaccines in young children and approaches for demonstrating effectiveness in serogroup B vaccines. Representatives from Novartis and Pfizer made presentations on new but differing approaches for developing effective therapies and new surrogates for demonstrating protection.
Novartis says it is discussing a “pathway to licensure” with FDA and “evaluating its phase 3 plans” for the US and other regions. But market approval of a meningitis B vaccine in the US may take much longer because Novartis and other vaccine makers now appear more interested in developing a combination vaccine that will cover all five meningitis strains.
To some extent, that decision reflects problems with reimbursement for new vaccines, which largely comes from public health agencies. Novartis received a blow in July when the UK’s Joint Committee on Vaccination and Immunisation advised against adding Bexsero to its routine vaccination program. The Committee is reconsidering that recommendation, which was based largely on cost-benefit considerations: whether it is worth the money to vaccinate some 800,000 infants a year when only 1800 cases of the disease are found in children in the UK each year, and there are concerns that the vaccine may be only 73% effective.
These developments have spurred more talk about Novartis selling its vaccine business, which has struggled to be profitable, according to market analysts. Novartis recently announced the sale of its blood transfusion diagnostics unit, which is housed with its vaccines unit.
Researchers and patient advocates for a more effective meningitis vaccine point out that cost-effectiveness studies often fail to assess prevention appropriately. They also fear that a final UK non-coverage decision for Bexsero could discourage vaccine research in general. Coverage certainly would be easier to justify for an all-strain meningitis vaccine, but that may involve years of more testing.
Congress gave final approval this week to new legislation to strengthen FDA authority to oversee large pharmacy compounders of sterile injectables and to require more comprehensive tracking of prescription drugs moving through the global supply chain. The House passed the the Drug Quality and Security Act in late September, but Senate action was delayed, first by the federal government shut-down in October and then by individual efforts to force a vote related to Obamacare.
But continued public outrage over deaths from contaminated injectables produced by large compounding pharmacies, along with rising concerns about counterfeit and unauthorized drugs entering the US market, managed to overcome the partisan stalemate on Capitol Hill to win strong approval for the measure. No one gets all they wanted from the legislation, but it provides more clarity and predictability to drug oversight programs and moves forward initiatives designed to enhance the safety and quality of medicines in the United States.
Alan Coukell, senior director of drugs and medical devices at The Pew Charitable Trusts, praised the bill as “meaningful” and said that efforts to block counterfeit and contaminated drugs will “help protect lives and alleviate these costs by ensuring that prescription drugs are safe, effective and of the highest quality.” President Obama is expected to sign the bill fairly quickly
As previously noted here, the first section of the bill clarifies FDA’s authority over drug compounding, which resolves questions raised by diverse federal court rulings on the issue. Pharmaceutical manufacturers gained legislative language specifying that compounders cannot produce drugs that are “essentially a copy of a marketed drug.” But the bill is not as strong as FDA and patient advocates had hoped, as it fails to set specific criteria to differentiate large commercial operations from local compounding pharmacies. The legislation instead relies on a voluntary registration system for large-scale compounders, which will have an impact only if large purchasers of compounded drugs insist that their suppliers meet FDA standards.
The main gain for manufacturers from the drug supply chain security section of the act is to pre-empt state pedigree laws, including the comprehensive California statute slated to go into effect in 2015. The new bill generally follows the Senate’s 10-year time-line for establishing an electronic, interoperable, unit-level drug tracking system. All drug packages will have to carry serial numbers in four years, and FDA will establish verification and traceability standards and provisions for data exchange.
The tracking system will include manufacturers, wholesaler/distributors and pharmacies, with some exceptions for small firms. In addition, third-party logistics providers such as Federal Express and UPS get a pass on keeping records and participating in investigations, which could create serious gaps in the tracking process.
Some critics blasted the bill for giving industry so much time to establish unit-level tracking and for imposing fairly weak oversight of compounders. But FDA, manufacturers, and policy makers seem pleased to gain enactment of any legislation at all. The long-term impact remains to be seen.
FDA is proposing to revise its rules to permit generic-drug manufacturers to initiate safety-labeling changes instead of waiting until the brand company takes action. The aim of the new policy is to inform consumers more quickly of emerging safety concerns, but it also could create confusion by allowing prescribing information to differ among generic and brand products.
Health plans that limit drug converge may encourage consumers to obtain medicines illegally, according to pharmacy experts. Marv Shepherd, director of the Center for Pharmacoeconomic Studies at the University of Texas College of Pharmacy and others noted at the Partnership for Safe Medicines Interchange in October in Washington that an increase in narrow health plan formularies that carry only one or two drugs per class or category will boost purchases of substandard, counterfeit and diverted prescription medicines through illicit operators. Patients accustomed to treatment with a certain drug may seek out other sources of supply if a streamlined plan fails to provide coverage for that medicine, explained Bryan Liang, anesthesiologist and law professor at the University of California San Diego.
Establishing a new Office of Product Quality in the Center for Drug Evaluation and Research (CDER) is a top priority for CDER director Janet Woodcock, and she plans to take charge of the operation personally when it is established next year. Her much-discussed reorganization effort is not just an exercise in moving around boxes, but aims to ensure the delivery of quality medications to patients, she explained at the Generic Pharmaceutical Association’s Fall Technical Conference in October.
Woodcock expects OPQ to become operational in 2014, and is moving forward with completion of a concept of operations for the new office, along with an organizational structure. But it is “not a done deal,” Woodcock observed at the ISPE annual meeting last month. She expects it will take at least six months for the new organization “to become real.”
One aim is to establish “one voice for how FDA regulations drug quality”––within CDER and in its relationships with other FDA of offices and other regulatory authorities. This will apply to new drugs, generics, over-the-counter products––biotech therapies and small molecules alike.
OPQ will form specialized staffs for product review and for inspections, with specific units to handle active pharmaceutical ingredients, new drugs, biotech products, and “life cycle drugs” (i.e., generics). OPQ also will bring together microbiologists for all products to provide a unified approach to microbiology.
A new Office of Surveillance in OPQ will oversee quality performance at facilities through pre-approval and routine inspections, with an eye to evaluating if an operation meets performance metrics that indicate a quality operation. And a Policy Office will issue guidance and regulations, while ensuring consistency in CDER actions. Surveillance will be enhanced by CDER gaining more complete information on its inventory of establishments, an undertaking that ideally will lead to less frequent field inspections.
Another theme is to “mitigate risks” by applying appropriate measures and analytical methods to different products. Woodcock expects risk assessment for every product to evaluate critical issues and employ statistically valid sampling.
The main aim of this reorganization is to achieve a “culture of quality in industry,” Woodcock said at the ISPE meeting. These plans will require considerable change within FDA and in industry, and manufacturers, she added, have to recognize that there is a “cost to poor quality.”
Officials from FDA and the National Institutes of Health (NIH) were scheduled to explain developments in clinical trial registration and transparency at the Drug Information Association’s conference on Clinical Trial Disclosure in Bethesda, Md. this week. They sent in slides, and one HHS official even pre-recorded his presentation. But the government shutdown kept them from showing up in person.
Public outrage over deaths from contaminated injectibles produced by large compounding pharmacies, along with rising concerns about counterfeit and unauthorized drugs entering the U.S. market, managed to lift the stalemate on Capitol Hill long enough to generate agreement on reform legislation. After months of public hearings and negotiations, Democrat and Republican leaders of the House Energy & Commerce Committee and the Senate Health, Education, Labor and Pensions Committee unveiled a compromise bill last week. No one gets all they wanted from the Drug Quality and Security Act, but it provides more clarity and predictability to drug oversight programs and moves forward initiatives designed to enhance the safety and quality of medicines in the U.S.
Healthcare spending will rise modestly in the US over the next decade, as economic growth picks up, health reform provides expanded coverage, and the population continues to age, according to an annual analysis from the Centers for Medicare and Medicaid Services (CMS). These trends similarly will boost expenditures for prescription drugs, but not as quickly as in previous decades.
Outlays for healthcare in the US have grown much more slowly over the past three years, largely due to an economic decline that deterred individuals from seeing doctors and to increased cost-sharing requirements for the privately insured. Minimal growth is continuing this year, but expenditures will begin to rise in 2014, boosting the average growth rate for national health spending to 5.8% through 2022, according to the National Health Expenditure Projections from the CMS Office of the Actuary and published by Health Affairs. Much of the spending will come from public agencies, as healthcare financed by federal, state, and local governments reaches $2.4 trillion in 2022, nearly half of all national health outlays.
FDA commissioner Margaret Hamburg has formed a top-level working group to propose strategies for enhancing agency functions and processes, starting with the relationship between FDA Centers and its field force. The Program Alignment Group (PAG), announced Sept. 6, 2013, will seek to clarify the roles and responsibilities of product centers and the Office of Regulatory Affairs (ORA) to more effectively align practices, processes, and resources. The panel includes the deputy commissioners for food and veterinary medicine, for global regulatory operations and policy, plus the heads of ORA and all Centers to better coordinate inspection and oversight policies and programs throughout the agency.
Key issues are whether more specialization in FDA inspection and compliance functions would be beneficial, and how risk-based models and performance metrics may improve oversight and compliance outcomes. The agency also is looking for ways to achieve more efficient laboratory operations and to coordinate training for ORA and Center staffs.
Hamburg further explained at a conference on biomedical research the next week that her reorganization effort reflects the impact of a more globalized world for medical product development and production. Historically, ORA has fielded generalists able to inspect and evaluate a broad range of regulated products, but the modern era may require a more specialized regulatory staff. And while these issues have been addressed periodically by FDA Centers, including the Center for Drug Evaluation and Research (CDER), the PAG will seek a more cohesive approach that considers the differences and needs of all regulated product areas.
CDER director Janet Woodcock, who is on the PAG, sees its mission paralleling her initiative to modernize how CDER regulates pharmaceutical quality. Woodcock seeks to establish an Office of Pharmaceutical Quality (OPQ), which similarly would coordinate drug compliance activities with ORA and take steps to clarify roles and responsibilities of CDER offices and to establish metrics and accountability.
At the PDA/FDA joint regulatory conference Sept. 16, Woodcock emphasized that CDER has to change the way it regulates industry to ensure an agile manufacturing sector that can reliably produce quality medicines, with less extensive agency oversight. One innovation would be to reorganize the review of the manufacturing portion of drug applications according to dosage forms and their predictable “failure modes.” Most product recalls, she noted, involve formulation design problems, such as particulates in parenterals and dissolution failures with solid oral products. This approach will involve setting clinically relative specifications and identifying what changes raise risks for drug safety and efficacy – and what do not.
The PAG is slated to give Hamburg an initial plan for operational changes by early December. And CDER hopes that OPQ will become a reality early next year, said Keith Webber, acting director of CDER’s Office of Pharmaceutical Science, at the PDA conference. The reorganization process is slow, as CDER’s OPQ proposal requires approval by HHS officials and has to be vetted by the Office of Management and Budget; some members of Congress also may want to review how the changes could affect drug shortages and patient access to medicines.