If FDA is going to establish standards for assessing the quality of manufacturing sites and products, it should seek data on a few well-defined measures that reflect longer-term results and trends, rather than “snapshots of current numbers.” And such metrics should include more leading—vs. lagging—indicators to reflect a firm’s commitment to continuous improvement in production processes. Those recommendations come from a PDA “points to consider” paper, written to help FDA set standards to measure product quality and manufacturing capabilities.
Moving fast to bolster its authority over compounding pharmacies that operate as manufacturers of prescription drugs, FDA is urging “outsourcers” to register, seeking state support, and moving to issue more rules and guidance. The agency is pleased that 14 outsourcers registered through mid-January. The number is small, considering that an estimated 3000 compounding pharmacies make sterile injectible drugs, but this initial activity reflects FDA’s fast action in implementing the Drug Quality and Security Act (DQSA), which was enacted less than three months ago.
As expected, FDA approved only 27 new molecular entities (NMEs) in 2013. There was no late-December surge in approvals to bring the tally closer to the near record of 39 innovative new drugs approved in 2012. In addition, the Center for Biologics Evaluation and Research (CBER) approved eight novel products, including innovative influenza vaccines and a number of blood products.
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.