Angie Drakulich was editorial director of Pharmaceutical Technology.

Angie Drakulich

The US Food and Drug Administration posted on its website the minutes of the latest meetings between the agency and industry, and among stakeholders, regarding the reauthorization of the Prescription Drug User Fee Act V. The meetings were held Nov. 17–18. 

Participating in the industry meeting with the FDA Centers for Drug Evaluation and Research, and Biologics Evaluation and Research, were Pfizer’s Hilary Malone, BIO’s Sara Radcliffe, and PhRMA’s Theresa Mullin. The primary goal was to discuss proposals related to human drug review timelines. 

According to the minutes, both industry and the agency expressed the need for more time during the review cycle of new drug applications (NDAs) and biologic license applications (BLAs). Industry specifically would like more “substantive feedback during the application review cycle to better plan for AC [advisory committee] meetings, inform planning related to manufacturing scale-up, product launch, follow-on clinical development activities, and to potentially address issues identified in the applications.” For its part, FDA would like “more time to plan and conduct foreign inspections, address new authorities from the FDA Amendments Act (FDAAA) of 2007 such as risk evaluation and mitigation strategies (REMS) of greater complexity, plan for more frequent [AC] meetings, and address issues that can be resolved in the first cycle to reduce the need for multi-cycle reviews.” 

To address these needs, the agency proposed a review model for NDAs and BLAs that would include a late-phase meeting after primary and secondary reviews are complete. The late-phase meeting would provide a chance for the sponsor company and regulators to discuss any concerns identified during the agency review, including potential risk-management plans as well as any analyses or new data from the sponsor that may help resolve any noted deficiencies.

The agency also suggested submitting the AC background package to sponsors 21 business days prior to the AC meeting. This change would allow sponsor companies to prepare for the discussions in advance. To allow time for the late-phase communications being proposed, FDA suggested starting the review period after the two-month period in which FDA conducts filing and application validation activities. Agency representatives reiterated, however, that NDAs and BLAs must be fully completed upon submission for review. Otherwise, the review model proposed will not work.

FDA also noted the following during the meeting: unsolicited amendments would not be reviewed by the agency; any solicited major amendments could result in a three-month clock extension (a REMS submission could be considered a major amendment).  

The full minutes of the FDA-industry meeting can be found 

A separate stakeholder meeting focused on AC meetings, comparative effectiveness research (CER), off-label prescribing, REMS, and PDUFA enhancement. Representatives from FDA and various healthcare and nonprofit organizations were present. Participants discussed current practice and challenges in the above noted areas and offered a few suggestions.

For example, with regard to CER, FDA noted that comparative studies “often require enrollment of very large numbers of patients, making them very difficult and expensive to conduct, particularly in the case of demonstrating a comparative advantage for a symptomatic benefit.” FDA participants noted that a randomized withdrawal trial design can demonstrate whether a new therapy is effective in patients who have failed existing treatments and pointed out that the information being collected in the agency’s Sentinel database [see 

] could be helpful with CER determinations down the road.

On the subject of REMS, FDA participants “acknowledged that concerns have been raised about REMS that involve only a Medication Guide and noted that the agency is currently working on a guidance to address those concerns,” according to the minutes. The agency is working to standardize REMS materials and facilitate the use of existing pharmacy systems to implement them. For stakeholders, the agency suggested that their involvement in preapproval discussions would be best served through AC meetings because otherwise, REMS are considered confidential. 

The National Health Council, one of the participating stakeholders in the meeting, discussed conflicts of interest and noted that these should be more transparent. At the same time, the Council suggested that conflicts be managed to ensure that the right expertise is available within ACs. The Union of Concerned Scientists also made suggestions regarding conflicts of interest such as making it easier for the public to track FDA progress on the matter. 

Other stakeholders, the Consumer’s Union, National Women’s Health Network, and the Union of Concerned Scientists/Scientific Integrity Program raised questions about the agency’s Sentinel Initiative and the level of resources being spent on the project. FDA responded, according to the minutes, that a PDUFA proposal may add resources to the Sentinel project. The full stakeholder meeting minutes can be read 

The fourth version of PDUFA expires in September 2012. FDA has been and will continue to hold meetings with industry and other patient and consumer groups until its final recommendations are due to Congress on Jan. 15, 2012. 

FDA Posts Minutes to PDUFA V Discussion Meeting”

Articles

The US Food and Drug Administration posted on its website the minutes of the latest meetings between the agency and industry, and among stakeholders, regarding the reauthorization of the Prescription Drug User Fee Act V.

PDUFA Discussions Continue, New Review Models Proposed

The US Food and Drug Administration issued late last week a new guidance for industry on impurities in drug products. The guidance provides recommendations on the type of chemistry, manufacturing, and controls (CMC) information sponsors should include in their abbreviated new drug applicatons (ANDAs) and related supplements regarding the reporting, identification, and qualification of impurities that are classified as 

  includes information about establishing acceptance criteria for degradation products (i.e., degradation products of the active ingredient or reaction products of the active ingredient with an excipient[s] and/or immediate container–closure system) in generic-drug products. The new guidance replaces the 1998 guidance of the same name. 

FDA issued the new guidance, according to the document, to update information on listing degradation products, setting acceptance criteria, and qualifying degradation products (e.g., thresholds and procedures) in ANDAs to be more in line with the 2006 revision of the International Conference on Harmonization Q3B(R) guideline, 

. Some sections, for example, in the 1998 draft guidance were removed because ICH Q3B(R) covers them.

The new guidance describes what to include in the drug-product specification of an ANDA for degradation products such as stability studies, chemical-development studies, and routine batch analyses. “It is important that the list of degradation products for the drug product specification be based on degradation products found in the batch(es) manufactured by the proposed commercial process,” states the guidance.  A rationale for including or excluding degradation products in the specification should also be part of the filing.

The guidance further identifies what it calls “specified degradation products,” which are defined as individual degradation products with specific acceptance criteria that can be 

pecified identified degradation products are recommended to be included in the filing’s list of degradation products “along with specified unidentified degradation products that are estimated to be present at a level greater than the identification threshold given in 

says the guidance. The guidance also discusses acceptance criteria, including using the levels set in the 

With regard to the qualification of degradation products, the document asks that sponsors include in their filings a rationale for establishing degradation-product acceptance criteria that includes safety considerations. Qualification thresholds and procedures for degradation products are also discussed.

Finally, the new guidance document includes a decision tree involving questions about toxicity studies, reference products, threshold limits and more, to help in the identification and qualification of degradation products in generic drugs.

The US Food and Drug Administration issued late last week a new guidance for industry on impurities in drug products.

FDA Issues New Guidance for Industry on ANDAs: Impurities in Drug Products

Many companies use tiered pricing models, also known as differential pricing, for the distribution of their pharmaceutical products. Tiered pricing involves offering a drug product at a lower price or percentage to populations in developing countries or least developed countries (LDCs), thereby making the product more accessible to populations in need.  

The strategy largely took off in 2000 with the launch of the Accelerating Access Initiative (AAI), a collaboration of global regulatory bodies, United Nations (UN) agencies, and the pharmaceutical industry. AAI used the UN human development index to determine eligibility for differential pricing and focused on antiretroviral drugs (ARVs) to treat HIV/AIDS. In addition, industry and UN leaders tied the initiative to efforts to meet Target 4 of UN Millennium Development Goal 8 (MDG 8), which calls for pharmaceutical companies to establish partnerships to provide access to affordable drugs in developing countries. 

Doha Declaration on Trade-Related Aspects of Intellectual Property Rights 

(TRIPS), allowed low-income countries to issue compulsory licenses to companies to manufacture patented drugs (i.e., generic versions) at less-than-market cost without the innovator's approval in cases of public health emergency tied to HIV/AIDS, malaria, and tuberculosis. (TRIPS has been extended to 2016, although WTO is looking into ways to provide extra flexibility so that countries unable to produce pharmaceuticals domestically can import patented drugs made under compulsory licensing (1)). In May 2003, the European Union passed regulation that enables exporters to deliver essential drugs at tiered prices to poor countries by making sure the goods are not diverted back to the European Union (i.e., ensuring that regular market prices remain intact within the EU).  

Most tiered-pricing programs still focus on ARVs as well as treatments for tuberculosis and malaria. The World Health Organization (WHO) monitors and tracks pricing through its global price-reporting mechanism. Differential pricing remains voluntary and most pharmaceutical manufactures have their own pricing schemes for determining which countries qualify for discounts and at what rate. Many pharmaceutical companies place countries into three groups (low, middle, and high income, see sidebar "Key definitions"). 

Merck (Whitehouse Station, NJ) was one of the first pharmaceutical companies to implement differential pricing for ARVs and began disclosing its prices in 2001 (2). Many other companies have followed suit. GlaxoSmithKline (GSK, London), for example, provides certain vaccines to LDCs at a 90% discount and offers its patented drugs to LDCs at a price no higher than 25% of the price paid in developed countries. The company is starting to modify its prices for middle-income countries as well (3). 

Roche (Basel, Switzerland) sells Tamiflu (oseltamivir) at a reduced price for government pandemic stockpiling and offers additional price reductions to low-income countries. The company also has donated nearly 11 million treatment courses of Tamiflu to WHO, including 650,000 pediatric treatments. 

Novo Nordisk (Bagsvard, Denmark) offers human insulin to LDCs at prices that do not exceed 20% of the average price in Europe, Japan, and North America (4). And Bristol-Myers Squibb has run a Global Access program since 2001 that provides the company's HIV medicines at no-profit prices to those regions most impacted by HIV and with limited ability to pay (mainly sub-Saharan Africa) (5). These are only a few examples of pharmaceutical manufacturers working to meet UN MDG 8. 

Despite the benefits that differential pricing provides those in need of medicines but who can't afford them, there has been some pushback to the approach over the years. For example, middle-income countries have demanded lower prices similar to those that the poorest countries receive, and some poorer countries have been reported to use various discount rates to barter and spark competition among drug manufacturers (2). 

As a result, some alternative pricing methods are being established. For example, a new GAVI funding mechanism is being tested. GAVI, an alliance involving the Bill & Melinda Gates Foundation, UNICEF, WHO, and the World Bank Group, aims to save children's lives and protect health by increasing access to immunization in poor countries. Launched in 2000, the alliance brings together various countries and donor governments with the vaccine industry, research and technical agencies, and civil society to fulfill its mission. In the summer of 2009, GAVI formally launched advance market commitments (AMCs) as a funding approach designed to stimulate the development and manufacture of vaccines for developing countries. When a company makes an AMC, it commits funding to guarantee the price of vaccines once they have been developed. The funding helps vaccine manufacturers carry out research, train staff, and build manufacturing facilities. Participating companies also make binding commitments to supply the vaccines at lower and sustainable prices after the donor funds for the initial fixed price are used.  

An pneumococcal AMC pilot program aims to prevent more than seven million childhood deaths by 2030. The governments of Italy, the United Kingdom, Canada, Norway, and Russia, as well as the Bill & Melinda Gates Foundation, committed $1.5 billion to the pilot, to which the World Bank has offered its support (6). And earlier this year, GSK and Pfizer (New York) agreed to supply as many as 300 million doses of their pneumococcal vaccines over the next decade to GAVI countries as part of the pilot program.  

 1.  WTO, "Intellectual Property: Protection and Enforcement," 

www.wto.org/english/thewto_e/whatis_e/tif_e/agrm7_e.htm

 2.  R. Bate, "Drug Pricing and Its Discontents," (AEI, Aug. 2007), 

 4.  IFPMA, "Novo Nordisk: Differential Pricing on Insulin," Developing World Health Partnerships Directory, 

 5.  IFPMA, "Bristol-Myers Squibb Global Access Program," Developing World Health Partnerships Directory, 

Tiered pricing is used throughout industry to help increase affordability and access to drugs in the developing world.

Global Healthcare on the Ground: Differential Pricing

  The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) issued on Nov. 19, 2010, a summary of its latest meeting. Two key outcomes of the meeting include the agency’s procedure on modified-release oral opioids and its procedures for reviewing certain biosimilars.

  With regard to opioid-based drugs, the committee finalized a re-examination procedure on modified-release oral opioid products for the management of pain at level III of the World Health Organization’s pain-management scale (i.e., the use of strong painkillers when other drugs have failed to control pain). Confirming its initial opinion [see 

], CHMP recommended the suspension of formulations using polymethacrylate-triethylcitrate controlled-release systems. The reason, according to the summary, has to due with the products' interactions with alcohol. CHMP also recommended harmonizing current warnings on these products regarding their use in conjunction with alcohol.

  On the topic of follow-on biologics, or biosimilars, CHMP adopted a draft guideline, 

Similar Biological Medicinal Products Containing Monoclonal Antibodies

. This guideline describes nonclinical and clinical testing requirements for drugs that contain monoclonal antibodies that also claim to be similar to a drug already on the market. The guideline, to be published on the agency’s website, will be open to public comment for the next five months. 

  Finally, the committee adopted decisions on various applications from industry, such as those proposing extending treatment options for certain drugs already on the market in the European Union, and for restricting the use of modafinil-containing medicines. The full CHMP summary can be found on the EMA 

The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) issued on November 19 a summary of its latest meeting.

EMA Committee Makes Decisions on Opioids, Follow-on Biologics

The European Medicines Agency published a draft 

 of questions and answers on postapproval change-management protocols  last week. Postapproval change-management protocols were introduced in the 2008 European Union legislation EC (1234/2008). The Q&A is meant to outline general principles for using and implementing the protocols.

The document defines a postapproval change-management protocol as “specific changes that a company would like to implement during the lifecycle of the product and how these would be prepared and verified.” The protocol is meant to take a “stepwise approach” including  early and later evaluation of key data about the postapproval product change.

According to the document, drug manufacturers should submit to EMA as part of a marketing authorization application (or as a stand-alone variation) the relevant data needed to demonstrate that they have "acquired adequate knowledge to prepare and manage the impact of the change." For example, the protocol may include a risk assessment of the effect of the change on product quality and a description of the studies to be performed to assess the effect of the proposed change on product quality. Other examples are included in the draft Q&A.

The Q&A also discusses how and when the change should be implemented after EMA approves the protocol, and what types of changes apply. The document notes that the types of changes to include in this submission would “depend on the complexity of the product and its manufacturing process, as well as the understanding that the company has gained about them.” The Q&A goes on to say that “it is strongly recommended that companies submit postapproval change-management protocols only for those changes that they are highly likely to implement and whose feasibility has already been investigated and is supported by relevant data.”

Finally, the draft document addresses how to handle multiple changes and the logistics of submitting information to EMA. Comments on the draft are due on Feb. 28, 2011.

The US Food and Drug Administration issued a 

 for industry on chemistry, manufacturing, and controls (CMC) postapproval manufacturing changes this past June. The US draft guidance focuses on changes that are considered to have minimal effect on product quality and therefore can be reported to the agency through annual reports. More significant changes to approved new drug or abbreviated new drug applications (NDAs or ANDAs) follow reporting lines under the agency’s 2004 guidance on 

and section 506A of the Federal Food, Drug, and Cosmetic Act.  

The European Medicines Agency published a draft list of questions and answers on postapproval change-management protocols last week.

EMA Issues Draft Principles on Postapproval Change Management

The growth in pharmaceutical outsourcing is creating a more complex and risky supply-chain environment, according to a report issued last week. The 

Achieving Global Supply Chain Visibility, Control & Collaboration in Life Sciences: Business Imperative, Regulatory Necessity

, was cosponsored by Pricewaterhouse Coopers (PwC), IBM Business Analytics, and Camstar Systems, and published by Axendia, a life-science and healthcare analyst firm. As a result of this changing environment, states the report, pharmaceutical and life-science executives are on “high alert” and should consider adopting a new approach to controlling supply-chain risks.

One-hundred-and-twelve industry executives from pharmaceutical, medical device, and biotechnology companies worldwide participated in the survey. Fifty percent of survey respondents said that raw materials sourced outside of the United States present the greatest vulnerability in the supply chain, and 61% said that contaminated or nonconforming raw materials are likely to be the top threat over the next five years. 

Part of the cause for concern is that drug development is moving more and more to sites in developing countries such as China, India, Mexico, and Brazil—also pharmerging countries—which  involves more risk. Key survey findings, according to a PwC Health Industries Group press release, include the following:

Ninety-four percent of survey respondents believe that global product sales outside the US will increase in the next few years, while 78% said global sourcing outside the United States will increase and 76% said their global manufacturing outside the US will increase. 

Forty-four percent of respondents believe that the growing threat of counterfeiting will be a business risk in the next five  years; 35% say the same of illegal product diversions. 

Only 25% of respondents share common practices and information with suppliers, and only 3% have access to suppliers’ data in real time.

Nearly 60% of industry executives said that they are concerned about the willingness of suppliers to provide information to address regulatory requirements, and 44% are concerned about their distributors’ willingness to provide information needed to meet these requirements. 

Survey participants noted four hurdles to implementing track-and-trace technology: cost; difficulty of implementation; lack of industry standards; and lack of regulatory requirement and guidance. 

Industry executives said that their preferred method for creating best practices around standards and guidance is through industry consortium. 

“With manufacturing, sourcing, and the sale of medical products expected to increase dramatically in the emerging markets, the geographical expansion of the supply chain will make it more difficult to manage, as will the industry’s changing product mix,” said Wynn Bailey, PwC pharmaceutical and life-sciences advisory services partner. “In order to meet the demands of globalization, the pharmaceutical supply chain will need to become much more flexible, with different manufacturing routes and distribution channels for different kinds of products. Companies will need to implement new strategies, processes, and technology to proactively reduce and control risks.” 

In this regard, the report’s authors suggest the following road-map components to a safer pharmaceutical supply chain:

On-demand visibility (e.g., of systems and supplier visibility)

Control over the complete supply network (e.g., metrics and track-and-trace)

Collaboration (i.e., among industry, regulators, suppliers, and internally).

More details about each component are described in the full report.

New Report Addresses Pharma Execs’ Top Supply-Chain Concerns

The growth in pharmaceutical outsourcing is creating a more complex and risky supply-chain environment, according to a report issued last week.