Pharmaceutical Technology

 in the United States that contains measures to strengthen the ways in which drug shortages are dealt with. The US FDA is also taking action by asking companies to alert them as to possible drug shortages so that it can prepare back ups. But what about other parts of the world?

Drug shortages are not unique to the United States. The United Kingdom is also currently struggling with severe shortages of prescription medicines. In the US, many shortages have been attributed to plant closures or manufacturing problems, but in the United Kingdomthe shortages are being caused for a different reason: parallel trade.


Parallel trade, which is legal in EU law, involves products intended for the UK market being exported to other EU countries where they can often be sold at higher prices. This practice is common throughout Europe and has caused drug shortages in several countries over the years, impacting both patients and pharmacists who subsequently have to spend time sourcing medicines rather than performing other clinical and public health services.

Last week, the UK’s All Party Pharmacy Group (APPG) published a 

 detailing the results of an inquiry into drug shortages, which have plagued the UK for four years. The inquiry investigated the causes of the shortages, the problem they have caused, the effectiveness of efforts to tackle the problem and potential solutions. Occasional supply problems caused by manufacturing issues were not a focus of the inquiry as they have already been identified and there are contingency arrangements to deal with them.

But unfortunately there is no simple solution. The United Kingdom has already tried to solve the problem by implementing quotas and other supply mechanisms, as well as issuing best practice documents, but these have proven ineffective. The UK’s Medicines and Healthcare products Regulatory Agency has also pledged to address the shortages, but a lack of market data means that it is difficult to know exactly which products are in short supply and who is exporting them.

The report also added, “We have detected an air of resignation among those responsible. The problem of shortages has been dismissed variously as either inevitable, or as having been inherited from the previous Government. The Department of Health has also seemed reluctant to take action without having hard evidence…”

One drastic suggestion in the report is to put a stop to the exports. European law allows for the free movement of goods across EU borders, but the report claims that there it is possible to exempt certain goods if their free movement threatens public health. The report urges the government to at least consider this exemption.

In addition, the report poses other recommendations including:

The UK government must state that the interest of patients comes first ahead of the free movement of goods.

The MHRA needs to enforce obligations on those with licenses to conduct wholesale activities.

There needs to be improved and more regular collaboration between the Department of Health, the MHRA and supply chain representatives.

The paucity of market information needs to be addressed urgently.

Quota arrangements need to be simpler, less burdensome for pharmacists, more transparent and more sensitive to local variations in demand. A task force should be established to deal with this issue.

The APPG has invited the Department of Health to provide an update in six months’ time about its progress in tackling the shortages.

Articles

Parallel Trade Fuels UK Drug Shortages

The world of drug development is littered with early-phase failures: drugs that were shown to be safe in Phase I trials, but which failed to show efficacy later on. The failure of a drug at this early phase might not mean that there’s anything wrong with the compound. Rather, a failure might mean that the mechanism by which the drug acts was not of benefit in the disease against which it was tested.

A handful of these drugs are being pulled from the shelves and given a second chance in a new initiative 

 earlier this month. NIH’s new National Center for Advancing Translational Sciences (NCATS) is partnering with Pfizer, AstraZeneca, and Eli Lilly, which have agreed to make select compounds available for a pilot initiative to test promising compounds for new indications.

A total of $20 million will be used from NCATS’ budget to fund the initiative. Scientists may apply for research grants of up to three years duration for preclinical and clinical feasibility. Industry partners will supply around 20 compounds to participating researchers, as well as access to related data. The program also incorporates template agreements designed to streamline the legal and administrative process for participation, and a framework for handling intellectual property used or developed within the program.

In times of shrinking pharma R&D budgets, this is just the type of project by which industry can capitalize on relationships with academia. In the release, Jan Lundberg, PhD, executive vice-president, science and technology, and president, Lilly Research Laboratories, sums it up. “Discovering and developing new medicines, regardless of the therapeutic area being studied, is a complex and expensive process and we look forward to collaborating with the NIH and academia for the benefit of the patients we all serve.”

NIH Scientists Hope to Teach Old Drugs New Tricks

Drug shortages, particularly those for sterile injectable drugs, took center stage last year. In response, industry and the federal government, including FDA, took steps to address the problem. Progress has been made, and Congress is further evaluating if additional steps need to be taken.

Late last month, the Senate Health, Education, Labor and Pensions (HELP) Committee approved the Food and Drug Administration Safety and Innovation Act. The bill, which now goes to the full Senate for approval, reauthorizes the FDA user-fee program and also contains measures to strengthen ways to deal with drug shortages. The bill proposes revising the timing of advance notifications of possible shortages, requiring a strategic plan on shortages, broadening the definition of what constitutes a meaningful disruption of drug supplies, and creating a process for physicians and others to report evidence of shortages, as outlined by the American Medical Association (AMA) in analyzing the bill. Industry groups, such as AMA and the American Society for Health-System Pharmacists, support these measures.

 before the Subcommittee on Health of the House Committee on Energy and Commerce, which also is considering  measures to address drug shortages, FDA Commissoner Margaret Hamburg outlined the progress made in reducing drug shortages. Last October, President Barack Obama issued an Executive Order that directed FDA and the Department of Justice to take action to reduce and prevent drug shortages. Since the issuance of the Executive Order, FDA has successfully prevented 118 drug shortages and reduced the number of drug shortages. According to Hamburg’s blog, 42 new drugs in shortage have occurred in 2012 thus far compared to 90 new drugs in shortage in a comparable time period last year.

In her testimony, Hamburg outlined FDA efforts. When it learns of a potential shortage situation, the agency works directly with the affected manufacturer in several ways: developing temporary workaround solutions to manufacturing or quality issues; consulting with the manufacturer to resolve the underlying problem; or helping the manufacturer find additional sources of raw materials. It also expedites the review of submissions by the manufacturer that may alleviate the drug shortage while continuing to meet safety standards, which may include requests to extend the expiration date of products, make manufacturing changes to increase capacity, use a new raw material source, or change product specifications. FDA can also use its regulatory discretion for a manufacturer to continue marketing a medically necessary drug if the manufacturer can develop a method to resolve a quality issue prior to the drug’s administration. In addition to working with the affected manufacturer, FDA also does the following: works with third parties to determine whether they can help avoid or minimize the shortage; expedite reviews of generic applications for products facing potential shortages; and in certain situations, when a shortage cannot be resolved immediately, FDA can use its regulatory discretion for the temporary import of non-FDA-approved versions of critical drugs after ensuring there are no significant safety or efficacy risks for US patients.

These measures have had impact, but a question is whether more systematic means should be in play. Some commentary on this subject have suggested national stockpiles, such as those used for vaccines, be used to avert shortages. Whether this is an appropriate solution is unclear. What is clear, however, is that strengthening regulatory oversight to prevent or reduce drug shortages is an important goal for industry and consumers alike.

Drug Shortages Still in Focus

Apr. 16, 2012 marked the closing date for submitting comments on FDA’s draft guidance documents clarifying the approval process for biosimilars. More than 35 pharmaceutical companies, trade associations, and patient advocacy groups submitted public comments on the guidance documents, which are available 

A careful slog through the comments, revealed a few common issues, but also some topics that reflected the commentator’s industry outlook. Both BIO and PhRMA, industry trade groups, commented on the importance of protecting the innovator’s data until the period of exclusivity had expired, and also requested that the criteria for granting exclusivity be further clarified.

More than a few of the commentators asked for clarification around interchangeability. The guidance document has little detail on the topic, other than defining it as an approval designation permitting free substitution with the innovator product. Companies including Elan, Bayer, and Novo Nordisk asked that the agency provide more detail around the requirements for interchangeability, both in terms of product characterization and the sequence of steps to follow to obtain that designation.

While the abbreviated biosimilars pathway is intended to reduce the amount of clinical testing required for approval, there was a call from several commentators, including Elan, Novo Nordisk, the Alliance for Safe Biologic Medicines, and Amgen to preserve some requirements for clinical studies to ensure patient safety. According to Elan, there should be no cases where biosimilarity to a reference product, particularly for a monoclonal antibody, should be demonstrated by analytical means alone.

FDA will convene for a public hearing on May 11, 2012 to hear further commentary on the guidances, and I’m looking forward to hearing more on the topic. For those who don’t live near the FDA campus, the event is being webcast: more information 

A Few Comments on the Comments

Personalized medicine is gaining traction as scientists gain greater understanding of disease processes. Such an approach depends on the correct and reliable identification of an underlying biomarker, whether the biomarker is a genetic marker, receptor expressed by a tumor cell, or metabolite indicating some underlying condition, that can predict whether a patient is likely to respond to a particular therapy. Genomics and proteomics are methodologies involving large datasets of genetic or protein markers that are analyzed to produce an individual profile. Such methodologies are potentially quite powerful, but quite complex.

A recent high-profile cancer study conducted at Duke University relied on genomic analysis of tumors to tailor treatment to individual patients. Questions about the validity of the tests were raised at the outset of the trials by outside researchers, but the trials went forward anyway. In July 2010, more than 30 outside scientists asked the National Cancer Institute (NCI) to intervene and suspend the trials until the gene-expression tests could be reviewed adequately.

Wishing to avoid this type of expensive and potentially harmful error in the future, NCI and FDA requested that a study be performed by the Institute of Medicine (IOM) to recommend responsibilities and best practices for the investigators, research institutions, funders, regulators, and journals involved in development and dissemination of clinical omics-based technologies. The report was released on Mar 23, 2012, and identifies best practices to enhance development, evaluation, and translation of omics-based tests. The report also offers guidance for ensuring that these tests are appropriately assessed for scientific validity before they are used to guide patient treatment in clinical trials.

In the accompanying press release, chairman of the IOM committee Gilbert Omenn, professor of internal medicine, human genetics, and public health, and director, Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor says, “We hope that this report will help all members of the investigative team understand the entire pathway of translating omics discoveries into clinical tests and recognize and avoid the potential pitfalls at each stage. We believe that past problems, such as the Duke case, could have been prevented had a clearly defined process been available and been utilized. Scientific and clinical progress in omics test development will be accelerated if these recommendations are broadly adopted.”