Generic Prices Take Flight

P&T Journal - December 2014 - for a PDF copy of the published version go HERE.

The FDA Is Struggling to Ground Them

Over the past few years, safety and effectiveness have been the issues plaguing generic pharmaceuticals. But concern has largely faded about the quality of active pharmaceutical ingredients manufactured in places such as India or China, or the bioequivalence of products such as Budeprion XL 300 mg. Now a new series of question marks hovers over generic drugs.

The price of generics looms largest. Still prized for their low cost, some generics have lifted off into the dollar stratosphere—though admittedly they haven’t reached the moonlike some new brand-name drugs, such as Gilead’s Sovaldi. That said, the number of generics posting higher prices, and the height of those leaps, worry consumers, payers, and some members of Congress.

A variety of reasons account for the increases. Loss of momentary competition in a category because one manufacturer stops producing, for any number of reasons, comes into play. So does the dropping of product lines. New products in existing generic markets find the door to entry barred, sometimes by competitors already selling into that market, sometimes by a Food and Drug Administration (FDA) besieged by applications and understaffed to handle them.

The FDA must approve abbreviated new drug applications (ANDAs) filed by generic drug companies, and the agency was thought to be making big strides in light of $300 million a year in new user fees from generic companies thanks to the 2012 Generic Drug User Fee Amendments (GDUFA). The fees were supposed to guarantee faster approval, leading to lower costs to companies and lower prices for new drugs that would be introduced more quickly.¹ But some industry experts think that GDUFA has failed to deliver, and that the FDA has gone backward on approval speed.

Walter Jump, President of Cornerstone Regulatory (a consulting firm that works with both generic and brand-name companies), says that costs for industry have increased since the passage of GDUFA. “Nothing provided for in GDUFA will decrease costs to industry. Although the Generic Drug User Fee Amendments propose to reduce the current delays in the drug approval process, currently there is no proof that the delays in the current approval process are being addressed,” Jump says. In fact, the FDA’s ANDA backlog has increased. Currently, Mylan Inc. has 288 ANDAs awaiting FDA approval that represent $111.5 billion in annual brand sales, according to IMS Health. Forty-three of these pending ANDAs are potential first-to-file opportunities, representing $28.7 billion in annual brand sales for the 12 months ending June 30, 2014, IMS Health adds.

During a meeting at the FDA on September 17, 2014, called to air a number of GDUFA issues, David R. Gaugh, RPh, Senior Vice President for Sciences and Regulatory Affairs of the Generic Pharmaceutical Association (GPhA), said that in 2013, the median time for generic drug approvals jumped to 36 months and is projected to reach 43 months in 2014 once the final numbers are in.

Jump hypothesizes that the slowdown in approval times may be related in part to the need for more-experienced FDA drug reviewers to spend part of their time training new drug reviewers who have been hired thanks to the $300 million infusion. Such training will take time to ensure that all these new employees are consistent in their reviews.

“The generic supply chain has become very fragile. For many generic drugs, there are only a few suppliers,” says Adam J. Fein, PhD, of Pembroke Consulting, Inc. “Any supply shock to the system, such as a manufacturing problem or FDA action, can rapidly create a shortage because alternative capacity isn’t ramping up to meet demand.”

Tetracycline shortages, for instance, have resulted in much higher generic prices. Watson Pharmaceuticals stopped producing tetracycline tablets in December 2013 and was acquired by Activis PLC in 2014. Activis has not restarted production. As of October 2014, Teva Pharmaceutical Industries Ltd., a one-time producer of tetracycline, was no longer selling the product because of a raw material shortage. Heritage Pharmaceuticals Inc. markets the brand-name version of tetracycline, called Achromycin V. In October 2013, Heritage announced it was making available generic tetracycline HCl capsules in 250- and 500-mg strengths. Not surprisingly, then, with only one manufacturer in the game, the price of tetracycline 500-mg and 250-mg tablets increased from $0.05 and $0.06 per capsule in July 2013 to $8.59 and $4.26 in July 2014. Those are increases of 17,714% and 7,340%, based on pricing data from Drug Channels, a website written by Dr. Fein.²

The Importance of Generics

The importance of generics to slowing the growth of health care costs is obvious. The FDA has approved more than 8,000 generic equivalents to brand-name drugs; as a result, generics represent more than 85% of all U.S. prescriptions and have saved U.S. consumers and the health care system $1.5 trillion in the past decade alone, according to the GPhA.

For years, the discounted price of generics was the glittering jewel in their crown. Not any more. Escalating prices have hit hospital pharmacies, drug stores, and consumers alike. This year, Walgreens fired its chief financial officer and the president of its pharmacy, health, and wellness division because they underestimated the cost of generic drugs and overestimated pharmacy unit earnings for the fiscal year ending in 2016.

Insurance plans are responding in order to mitigate the price pressures. Dr. Fein states, “Some payers are already establishing a ‘nonpreferred’ or ‘more costly’ generic tier for products that have experienced significant inflation. If generic inflation continues, I expect to see more plans with multiple generic tiers.”

Hospitals are suffering from generic drug price increases, too, since drug costs for any inpatient “event” are bundled into the cost of reimbursement for that patient, whether Medicare, Medicaid, or a private insurer is paying. Any generic drug price increase will not be reflected in the global payment from private or public insurers, paid on the basis of a diagnosis-related group (DRG)—at least not any time soon. True, generic costs make up a tiny percentage of any DRG reimbursement. But over the course of a year, they may add up. Hospitals also face potential cost implications on the outpatient pharmacy side. “The average selling price for the generic will not be updated for up to six months after the actual price increase, meaning hospitals will have to pay the difference for that six-month period,” explains Bill Woodward, MS, RPh, Senior Director of Pharmacy Contracting for Novation, a contracting and information company that serves 100,000 members and affiliates of VHA Inc. and UHC, two national health care alliances; Children’s Hospital Association, an alliance of the nation’s leading pediatric facilities; and Provista, LLC.

Generic price increases have caught the attention of some in Congress. On October 2, Representative Elijah Cummings, ranking member of the House Committee on Oversight and Government Reform, and Senator Bernard Sanders, Chairman of the Subcommittee on Primary Health and Aging of the Senate Committee on Health, Education, Labor, and Pensions, sent letters to 14 generic drug manufacturers requesting information about the escalating prices they have been charging for generic drugs.³ “When you see how much the prices of these drugs have increased just over the past year, it’s staggering, and we want to know why,” says Cummings.

Huge Generic Price Increases

In their letters, Cummings and Sanders cited data from the Healthcare Supply Chain Association on purchases of 10 generic drugs by group purchasing organizations for which prices have skyrocketed in the past year. Among the citations:

• Albuterol sulfate, used to treat asthma and other lung conditions, increased 4,014% in price, from $11 to $434 for a bottle of 100 2-mg tablets.
• Doxycycline hyclate, an antibiotic used to treat a variety of infections, increased 8,281% in price for a bottle of 500 100-mg tablets (from $20 to $1,849).
• Glycopyrrolate, used to prevent irregular heartbeats during surgery, increased 2,728% in price for a box of 10 0.2-mg/mL, 20-mL vials (from $65 to $1,277).

It doesn’t appear that any of the 10 drugs cited in the letters are marketed by only one company, so competition should keep prices from breaking through the roof. But in some instances, that competition is limited. Albuterol sulfate is sold by Mylan and Mutual Pharmaceuticals. Doxycycline hyclate is sold by 10 companies, with three representing most of the market share. West-Ward, Inc., dominates the market for glycopyrrolate.

Mylan, Teva, and Lannett Company, Inc., are among the companies that received the Cummings/Sanders letter. The first two did not respond to a query asking for a response. In its 2013 annual report, Lannett said: “Gross profit improved considerably to $57 million from $39 million. As a percent of net sales, gross margin rose to 38% from 32%, with the increase primarily due to favorable sales mix, price increases, and enhanced manufacturing efficiencies.” Asked about the extent of product price increases, spokesman Robert Jaffe says, “Lannett’s management respectfully declines to be interviewed.”

Why the Price Hikes?

A number of factors can cause a spike in a generic price, justifiable or perhaps not. There are also reasons why drug prices won’t drop. A number of mega-consolidations have taken place in the industry over the past few years. One by one, generic companies are disappearing. Competition in each category is diminishing. Earlier this year, Mylan acquired Agila Specialties Private Ltd., giving Mylan a strong hold on the generic injectables market. In that instance, the FDA forced Mylan to divest drugs in a number of categories before it approved the acquisition. For example, Mylan divested etomidate injection, ganciclovir injection, and some other injectables to JHP Pharmaceuticals. Earlier this year, Par Pharmaceutical Companies, Inc., acquired JHP. Valeant Pharmaceuticals International, Inc., is trying to acquire Allergan, Inc., and promises, if successful, to put a plug in its research pipeline. Teva acquired Cephalon, Inc., in 2012. Also in 2012, Valeant bought Ortho Dermatologics, Inc., from Johnson & Johnson and Dermik Laboratories, Inc., from Sanofi.

New products are not entering the market as quickly as had been hoped in the wake of GDUFA passage. And when they do enter the market, it is after the manufacturer has spent more in development and regulatory costs than might otherwise have been necessary. The GDUFA was supposed to pave the way for eliminating ANDA approval backlogs by mandating, for the first time, that generic suppliers pay “user fees” to the FDA. In return, the agency committed to approving ANDAs—submitted when a generic company wants to sell a copy of a patented pharmaceutical—according to specified time frames. The fees amount to about $300 million a year. The GDUFA required the FDA to publish five guidance documents that lay out how the agency planned to meet the approval deadlines in its GDUFA “commitment letter.” For example, the FDA has committed to review and act on 90% of original ANDA submissions within 10 months from the date of submission in year 5 of the program, which begins on October 1, 2016.

Of course, generic companies themselves are responsible for many delays. They fight like Hatfields and McCoys over whether one or the other should have its ANDA approved, whether as the “first-time” generic in a category or as a new competitor to an existing generic. One example is Apotex Corporation’s filing of a citizen petition with the FDA in January 2014 to block Forest Laboratories’ generic version of Apotex’s Namenda XR (memantine hydrochloride extended release capsules). The Apotex drug was approved in June 2010 and first became available in June 2013. Apotex argued that since its drug only became available in June 2013, it would have been impossible, time-wise, for Forest to conduct the required bioequivalence studies. The FDA rejected the petition on June 12, 2014. Ross Maclean, PhD, Senior Vice President for Scientific and Regulatory Affairs at Apotex, did not return a call asking for comment.

In filing its citizen petition, Apotex was trying to prevent Forest from claiming 180-day market exclusivity, which has price implications, too. (Forest disappeared last February when it was swallowed by Actavis). The 180-day period was put into law in 1984 as part of the Hatch-Waxman Drug Price Competition and Patent Term Restoration Act of 1984. It is supposed to function as an incentive for a generic company to be the first to submit an ANDA for a brand-name drug coming off patent. Since GDUFA was signed into law, at least 19 first applicants have forfeited 180-day exclusivity because they failed to get timely FDA approval, according to the GPhA. Typically, once a paragraph IV ANDA is filed, a 30-month clock starts if the brand-name company challenges the generic company’s right to sell a product because of patent infringement. If the FDA fails to review an ANDA prior to the expiration of the patent being challenged, the 180-day exclusivity may be lost. With the patent or patents expired, any generic company can sell a copy of that brand-name drug. So that 180-day “incentive” is not much of an incentive these days.

The confusion over exclusivity can affect pricing in opposite directions. Michael D. Shumsky, an attorney for Kirkland and Ellis, LLP, and an outside counsel to Teva, explains that if a first generic applicant believes it is entitled to exclusivity, it typically will produce enough product to satisfy the entire market. But it could wind up with substantial inventories that it will never be able to sell if the FDA subsequently holds that the applicant is not entitled to exclusivity. The resulting losses are then passed on to consumers in the form of higher prices, which undermines the statute’s basic goal of lowering prescription drug costs.

The reverse is also true. If a first generic applicant believes that the FDA will find it has forfeited or otherwise lost its exclusivity, it may not prepare sufficient quantities of a product to supply the market—leaving it unable to fulfill consumer demand in the event that the FDA finds the applicant has maintained its eligibility for exclusivity. That likewise increases costs for consumers.

The GDUFA: Promises and Pitfalls

The 180-day exclusivity period and the FDA’s policies for granting it were among the topics on the agenda of the FDA’s September 17 meeting. Also up for discussion were the five draft guidance documents the agency has issued as follow-ups to its GDUFA commitment letter. At the time of the GDUFA’s passage in 2012, more than 2,700 generic applications were awaiting FDA approval, and the average approval time for an application stretched beyond 30 months—five times longer than the statutory six-month review time called for by the Hatch-Waxman Act. That backlog had been reduced to about 2,100 when Greg Giba announced his departure as director of the FDA’s Office of Generic Drugs (OGD) in March 2013. Giba, whose appointment had been announced only the previous July, quit because a reorganization left him with less resources than he felt he needed. A new permanent director has not been appointed.

But the ANDA backlog (Figure 1) remains a cause célèbre for the generics industry. So does its impact on company costs, which affects product pricing. The FDA has said several times that one objective of GDUFA was to reduce costs to generic manufacturers. But Jump, of Cornerstone Regulatory, says that costs for industry have increased since GDUFA’s passage:

In fact, since the law has gone into effect, user fees have been instituted, requirements for the production and submission of three registration batches for each product strength, and the refusal to accept stability data with less than six months of stability data have all increased the costs to industry. The potential for earlier approvals, which has not been seen to date, can at best only potentially increase industry revenue, but it cannot decrease development costs.

The September 17 meeting, held as the October 1, 2014, start of the first iteration of GDUFA timetables was looming, touched on five guidance documents the FDA had issued in draft form. They are supposed to give the industry a clearer idea of what the FDA expects in an ANDA in various areas. The five guidance documents are:

• ANDA Submissions—Content and Format of ANDAs⁴
• ANDA Submissions—Refuse to Receive for Lack of Proper Justification of Impurity Limits⁵
• ANDA Submissions—Amendments and Easily Correctable Deficiencies Under GDUFA⁶
• ANDA Submissions—Prior Approval Supplements Under GDUFA⁷
• Controlled Correspondence Related to Generic Drug Development⁸

Most of these draft guidances were published this past summer. They are too mind-numbingly arcane to discuss here. Suffice it to say that the response to most of the draft guidance documents has not been particularly positive. With regard to “Content and Format of ANDAs,” Jump complains, for example, that his clients “are dismayed” that the FDA is requesting that the cover letter contain the same information contained in the common technical document (CTD) and the 356h form. This is an unnecessary duplication of information. “Repeating the same information in multiple places only increases the chances that inadvertent mistakes can be made,” Jump states. “These inadvertent mistakes are frequently the cause of deficiency comments from the agency asking which information is correct.” The CTD is the international format for what should be included in the ANDA. For instance, manufacturing site and contact information are requested in the FDA 356h form and specific sections defined within the ANDA. Now companies will have to include that same data in a third place, the cover letter, increasing the chances that there may be inadvertent discrepancies among the three. An FDA reviewer might kick back the application for that reason.

The problem these days is that reviewers aren’t “kicking out” approved applications. “I agree there are some major issues at the Office of Generic Drugs,” says Bob Pollock, Senior Advisor and Outside Director to the board of Lachman Consultants. Pollock, who left the FDA in 1994 as Acting Deputy Director of the OGD, writes a blog on the Lachman website. “One thing that surprises me is that there is more emphasis on process, policy, and procedure. They also need more attention to moving the freight. Folks in the industry are scratching their heads, wondering when things are going to improve.”

Author bio: 

Mr. Barlas, a freelance writer based in Washington, D.C., covers topics inside the Beltway.

FDA Devotes New Resources To Upgrading Generic Drug Safety

P&T Journal
May 2014 - for a PDF copy of the published version go HERE.

But in Some Instances, the Industry Is Pushing Back

If one were looking for an example of why the Food and Drug Administration (FDA) appears increasingly concerned about the quality of generic drugs in the U.S., one need look no further than the Indian company Ranbaxy Laboratories. In the past few years, it has on its own and at the FDA’s insistence recalled bottles of atorvastatin calcium (generic Lipitor) and been barred from exporting to the U.S. products made at a plant in Toansa, India. In 2013, Ranbaxy, owned by the Japanese drug company Daiichi Sankyo, paid a $500 million fine and pled guilty to criminal charges of selling adulterated drugs and making false statements to the FDA.1

The FDA also banned sales in the U.S. from Indian facilities owned by a second Indian company, Wockhardt Ltd. In a long letter dated July 18, 2013, to Habil Khorakiwala, Wockhardt’s Chairman and Group Chief Executive Officer, Michael D. Smedley, Acting Director of the FDA’s Office of Manufacturing and Product Quality, wrote that FDA inspectors had found significant violations of current good manufacturing practice regulations at the Wockhardt plant in Aurangabad, India. The company “withheld truthful information, and delayed and limited the inspection,” Smedley added.2

Of course, Ranbaxy, Wockhardt, and other major generic manufacturers such as Teva Pharmaceutical Industries Ltd., Sandoz, Actavis PLC, Mylan Inc., Hospira Inc., Sanofi, Aspen Pharmacare Holdings Ltd., and STADA Arzneimittel AG are more often the good guys, selling important drugs at significant discounts to patented alternatives. Those lower prices ease the financial strain on millions of Americans every year. Generic pharmaceuticals fill 84 percent of the prescriptions dispensed in the U.S. but account for just 27 percent of the total drug spending, according to the Generic Pharmaceutical Association (GPhA).3

Despite their financial advantages to consumers, however, generics may have a greater chance than brand-name products of causing adverse reactions because so many are in use. When they do, they prompt headlines atop stories that often very quickly mention that the company making the offending drug is headquartered outside the U.S., along with most or all of its manufacturing plants. Questions about adequate FDA inspection of overseas facilities come up just as quickly thereafter. Eighty percent of active pharmaceutical ingredients are imported to the U.S., as are 40 percent of finished drugs, according to the FDA.4 There are no good statistics on what percentage of finished generic drugs are imported.

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Generic Firms Increase Foreign Manufacturing

Even U.S.-headquartered generics manufacturers are rushing to expand overseas manufacturing, especially in India. Of the major generics players listed above, only Mylan and Hospira are headquartered in the U.S. Three of Hospira’s six major manufacturing facilities are outside the U.S., including one in Irungattukottai, India. In 2012, Hospira acquired an “active pharmaceutical ingredient” manufacturing site and an associated research and development facility from Orchid Chemicals & Pharmaceuticals Ltd. Those Orchid facilities are located in Aurangabad, India. Hospira also has an unconsolidated joint venture with Cadila Healthcare Ltd., a pharmaceutical company in Ahmedabad, India. The joint venture operates a manufacturing facility outside of Ahmedabad.

Mylan has 18,000 employees worldwide, 8,500 of them in India. Lauren Kashtan, Mylan’s Senior Manager of Media Relations and External Communications, declines to say how much of Mylan’s manufacturing is done outside of the U.S. But clearly a significant portion is done in India, with that volume apparently on the upswing. Mylan has signed a marketing agreement with India’s Natco Pharma Ltd. for Natco’s glatiramer acetate pre-filled syringes. In December 2013 Mylan purchased the Agila Specialties division from Indian generics manufacturer Strides Arcolab.5 Just two months later, on February 19, 2014, Mylan announced that Agila Specialties was conducting a voluntary nationwide recall from hospitals of 10 lots of etomidate injection 2 mg/mL packaged in 10-mL and 20-mL volumes. The 10 lots were made by Agila Specialties Polska Sp.z.o.o in Warsaw, Poland. Some vials contained pieces of paper, identified as shipper labels.6

“With so many products coming from overseas, it is a big task to effectively monitor products manufactured overseas imported to the U.S.,” says Gregory Amidon, PhD, Research Professor of Pharmaceutical Sciences in the College of Pharmacy at the University of Michigan (UM), who worked for pharmaceutical companies for 28 years.

Aside from manufacturing quality, the bioequivalence of generics has also been a concern. Questions about generic bupropion were raised as early as 2007. In October 2012, the FDA announced that 300-mg Budeprion extended release (XL), manufactured by Impax Laboratories and distributed by Teva, was not therapeutically equivalent to the reference drug, Wellbutrin XL 300 mg. A year later, after four companies completed testing requested by the FDA, the agency announced that Watson Pharmaceuticals was voluntarily withdrawing its generic bupriopion HCl ER 300-mg tablet because it was not therapeutically equivalent to Wellbutrin. At the same time, the FDA said its testing had proven that generic bupropion formulations marketed by Actavis, Mylan, and Par were bioequivalent to Wellbutrin. (Activis and Watson had merged prior to the announcement.)7

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Hamburg Trip to India Yields Very Modest Results

Concerns about generic drug quality have been percolating at the FDA for years, of course. But new regulatory requirements, funding streams, and expanding generic use on private and public formularies have forced the FDA to step up the pressure it exerts on the industry. FDA Commissioner Margaret Hamburg, MD, took her first trip to India at the end of February. While there, she signed a statement of intent with her counterpart, the Drug Controller General of India, Gyanendra Singh, PhD.8 The statement is fairly general, and its import and impact have been somewhat diluted by comments Dr. Singh made after Dr. Hamburg’s visit. Dr. Singh said, according to a journalist participating in a conference call with Dr. Hamburg upon her return, that if he had to follow U.S. standards in inspecting facilities he “would have to shut almost all of those.”

Actually, there was no need for Dr. Singh to devalue Dr. Hamburg’s efforts. The statement of intent commits India to do very little of substance beyond information-sharing and scientific collaboration. There is no talk of hiring additional inspectors, improving quality standards, or anything of that nature. And the statement allows India to forego even potential softball actions when “taking into account the limitations of existing human and financial resources and within the parameter of domestic legal and administrative requirements. …” 8

Asked whether the FDA was perturbed by Dr. Singh’s comment, a spokesman says, “Within five years, we will be able to conduct biennial inspections for both domestic and foreign facilities, allowing us to identify any noncompliant players in the drug supply chain—wherever they are based—so we can focus on the generic drug industry worldwide.”

Five years is a long time when lives are at stake. Questions about the quality and safety of generics become more important by the day as formularies for Medicare, Medicaid, employer health plans, and Affordable Care Act plans for independents heavily weight their tier-one drug offerings with generics. The announcement by Eli Lilly & Company in late March that it was eliminating pay raises for most employees in 2014 reflects the growing dominance of generics. Lilly said the loss of patent protection for Cymbalta, its best-selling drug, and Evista opened the door to generic competition and an expected sales decline of 14 percent in 2014.

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GDUFA Fees Let FDA Expand Regulatory Reach

Congress was aware of the generic surge, as well as its potential for both health care savings and safety problems, when it passed the Generic Drug User Fee Act (GDUFA) in 2012.9 The law required generic manufacturers to pay fees to the FDA for the first time. The agency uses those fees (which came to $300 million in 2013) to finance critical and measurable enhancements in generic drug programs. Generic drug facilities, sites, and organizations around the world must provide identification information annually to the FDA.

The GDUFA dictated a number of FDA actions and indirectly led to others. In addition to a key proposed rule and a testing program farmed out to academic medical centers, the FDA has published a draft guidance explaining when the agency could “refuse to receive” an abbreviated new drug application (ANDA). Before marketing a new product, generic companies submit an ANDA, which must be approved by the FDA. The guidance, which has not been finalized, delves into important issues such as whether the agency will accept a claim that a generic is “bioequivalent” to its brand-name counterpart.10

A proposed rule issued last November by the FDA allowing generic companies to change their safety labeling before the reference brand-name product does so11 has been among the most controversial of the FDA’s recent actions. The reason for the proposed rule is that generic companies are as likely to be alerted to adverse reactions as brand-name companies. But under current law, only the brand-name company can submit a “changes being effected” (CBE-0) supplement to the FDA. That allows the company to make certain labeling changes without FDA approval: for example, to add or strengthen a contraindication, warning, or precaution, or to strengthen a statement about drug abuse or an instruction about dosage. Once the revised labeling goes into effect, all generic products on the market are required to make their labeling conform within 30 days. This policy dates back to 1982.

But because only the brand-name manufacturer can make CBE-0 labeling changes, only the brand-name company is liable in court for adverse reactions. Generic companies cannot be sued for failing to update labels. Under the FDA proposal, generic drug makers could be sued—a prospect that displeases them.

The generic industry is arguing that the change in labeling policy would create nightmares for pharmacists and others as generic companies selling the same active ingredient were freed to change the labels of their individual products in any way they wanted. Uniformity would not be required. A number of pharmacy groups, including the Academy of Managed Care Pharmacy, American Association of Colleges of Pharmacy, American Pharmacists Association, and American Society of Health-System Pharmacists, signed on to a letter that the GPhA originated in March to comment on the rule. They said they were most concerned about the dangerous confusion multiple labels would cause and about the increased costs of and reduced access to generic medicines for patients who need them most. The letter stated that pharmacists could be exposed to liability as well as the generic drug companies.12

Allison Zieve, Director of the Public Citizen Litigation Group, doubts the validity of the “labeling confusion” argument. “Numerous different newly discovered safety risks are unlikely to come to light for a single drug at the same time,” she states. To buttress the contention, she refers to classes of brand-name drugs where there are several competitors. Take the selective serotonin reuptake inhibitor class of anti-depressants, for example. Fluoxetine hydrochloride (Prozac, Eli Lilly), sertraline hydrochloride (Zoloft, Pfizer), and paroxetine hydrochloride (Paxil, GlaxoSmithKline) are sold by different manufacturers. “We do not see the manufacturers discovering a variety of new safety risks all at about the same time,” she explains. “If several manufacturers submit changes at or near the same time, the changes are likely to address the same risk—and it will hardly confuse physicians and patients if, for instance, one generic warns that its drug ‘has been associated with inflammatory bowel disease in patients without a prior history of intestinal disorders,’ while another warns that ‘long-term use is associated with serious intestinal problems, including ulcerative colitis and Crohn’s disease,’ and a third warns that ‘patients taking this product should be monitored closely for signs of inflammatory bowel disease.’ ” 13

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Guidance Would Turn Back Flawed ANDAs

Labeling also comes up in the context of the draft guidance on “refuse to receive” that the FDA issued last October.10 This guidance, which the FDA has yet to finalize, was issued as a result of a GDUFA provision. It describes what should be included in an ANDA and highlights serious deficiencies that may cause the FDA to refuse to receive an ANDA. A refuse-to-receive decision indicates that the FDA has determined the ANDA is incomplete on its face, usually because of omissions. The draft guidance covers labeling, chemistry, and bioequivalence issues. Guidance, however, is advisory; the FDA cannot penalize a company for violation of guidance, as it can for violation of rules.

Underlining concerns about generic quality and safety, the draft points out that the FDA office of generic drugs refused to receive 497 ANDAs between 2009 and 2012. “Recent data underscore the need for improvement in the quality of original ANDA submissions,” the draft states. In 2012, of the 100 ANDAs that the office of generic drugs refused to receive, 40 were refused because of serious bioequivalence deficiencies, 36 because of serious chemistry deficiencies, 13 because of format or organizational flaws, six because of clinical deficiencies, four because of inadequate microbiology (sterility assurance) information, and one because an incorrect reference drug was cited. Those 100 accounted for approximately 10 percent of the ANDAs the agency received in 2012.10

The draft makes some minor and potentially major changes in current FDA policy. “There are several new criteria presented in the guidance document that will require ANDA applicants time to revise product designs and development strategies,” says David R. Gaugh, RPh, the GPhA’s Senior Vice President for Sciences and Regulatory Affairs. He is concerned, for example, with new guidance for oral liquid product formulations. “It would be inappropriate to require ANDA applicants to reformulate products, repeat clinical studies, and potentially forfeit a first-to-file opportunity by imposing the new refuse-to-receive criterion without ample time to adjust to the new standard,” he emphasizes.

The guidance says the FDA would reject an ANDA if it contains 10 minor deficiencies or one major deficiency. The sponsor may decide to submit additional materials to correct the deficiencies, but the resulting amended ANDA will be considered a new ANDA submission, received as of the new date and requiring a new GDUFA fee.

The “10-or-more” standard perturbs a number of companies. “Apotex is of the opinion that assigning a specific requirement on the total number to the deficiencies in the ANDA submission creates variability,” says Kiran Krishnan, Vice President of U.S. Regulatory Affairs for Apotex Corp. “Apotex is of the opinion that the number and nature of the deficiencies should not be used as a threshold to refuse an ANDA without giving the firms an opportunity to justify.”

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Questions on Testing Requirements for Generics

Still, some industry experts believe the FDA needs to require more from generic companies before approving ANDAs. “The current standards, criteria, and regulations governing approval and monitoring of generic drugs are inadequate,” say pharmacologist Joe Graedon, MS, and medical anthropologist Teresa Graedon, PhD. The Graedons write a syndicated newspaper column, host a health-talk show syndicated on public radio, and are founders and directors of the website www.PeoplesPharmacy.com. Their June 2013 comment letter responded to an FDA request for input on the agency’s generics regulatory science initiatives.

The major challenge generic companies face in seeking FDA approval of their ANDAs is proving their products are bioequivalent to the reference product. That involves dissolution testing: The rate at which a drug dissolves from a dosage form is measured, typically in the same medium used by the reference company’s product in its dissolution testing. The results can be used to determine whether the generic will have the same potency in a patient’s body as the reference drug. At least that is the theory—that an in vitrotest can predict in vivo results. “But that translation doesn’t work reliably in all cases,” states Dr. Amidon, the Michigan professor who worked for major drug manufacturers for nearly three decades and now directs UM’s Pharmaceutical Engineering Program. His program has received money from the FDA to develop and check new dissolution test methods and computer modeling techniques that may prove more accurate for predicting in vivo results.

Better dissolution methods and computer modeling might allow the FDA to waive in vivo bioequivalence testing, which it already does for some generics. But even some generic companies oppose easing those requirements. For example, Teva submitted a petition to the FDA in December 2013 pleading with the agency to require immunogenicity testing for companies submitting ANDAs for its branded product Copaxone (glatiramer acetate injection), a drug for patients with relapsing– remitting multiple sclerosis. The Teva petition asked the FDA not to provide any waiver of in vivo bioequivalence testing because Copaxone is a colloidal suspension rather than a true solution. In January 2014, Teva published data in the online scientific journal PLOS ONE purporting to show significant differences in biological and immunological effects between Copaxone and a generic glatiramer acetate marketed in India by Natco Pharma Ltd. Teva argued the differences have potential clinical ramifications.14 Natco and Mylan have filed an ANDA for glatiramer acetate injections, as have Momenta Pharmaceuticals and Sandoz. There has been patent litigation between Teva and the other two teams for years. The Copaxone patent expires in 2015.

Sandoz has not started manufacturing generic glatiramer acetate injections, of course, and it is not clear when and where that manufacturing will take place. The company has manufacturing sites in India. But Sandoz has had plenty of trouble with the FDA over its U.S. manufacturing sites, proving that generics manufacturing quality is a worldwide issue. The FDA issued warning letters to Sandoz manufacturing sites in Colorado, North Carolina, and Canada in 2011.15 In 2013, Sandoz, the world’s second-largest generics manufacturer, announced that it was recalling injectibles manufactured in Austria because of particles in vials.

So even with its new GDUFA authorities and funds, the FDA has its hands full ensuring the safety and effectiveness of generic drugs. The manufacturers take their responsibilities seriously, no question about that. But can they ever be serious enough?

Author bio: 

Mr. Barlas, a freelance writer based in Washington, D.C., covers topics inside the Beltway.

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REFERENCES

1. FDA. Regulatory action against Ranbaxy. Available at: http://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/enforce-mentactivitiesbyfda/ucm118411.htm. Accessed March 28, 2014.

2. FDA. Wockhardt Limited 7/18/13: warning letter. Available at: http://www.fda.gov/iceci/enforcementactions/warningletters/2013/ucm361928.htm. Accessed March 28, 2014.

3. Generic Pharmaceutical Association. Comments of the Generic Pharmaceutical Association for Docket No. FDA–2012-D-0880-0006, Draft Guidance for Industry Generic Drug User Fee Amendments of 2012: questions and answers. Available at: http://www.gphaonline.org/media/wysiwyg/cms/GPhA_GDUFA_Q_A_Response_2.pdf. Accessed March 28, 2014.

4. FDA. Global initiative. Available at:  http://www.fda.gov/AboutFDA/GlobalInitiative/default.htm?utm_source=fda&utm_medium=website&utm_term=GlobalizationReport&utm_content=f1&utm_campaign=HomePageSpotlight. Accessed March 28, 2014.

5. Mylan. Mylan completes acquisition of Agila to create leading global injectables platform. Available at: http://investor.mylan.com/releasedetail.cfm?ReleaseID=811637. Accessed March 28, 2014.

6. FDA. Agila Specialties Private Limited initiates voluntary nationwide recall of 10 lots of etomidate injection 2 mg/mL – 10 mL and 20 mL due to the presence of particulate matter and/or illegible and missing lot number and/or expiry date. Available at:  http://www.fda.gov/Safety/Recalls/ucm386547.htm. Accessed March 28, 2014.

7. FDA. Update: Bupropion hydrochloride extended-release 300 mg bioequivalence studies. Available at: http://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm322161.htm. Accessed March 28, 2014.

8. FDA. Statement of intent between the Food and Drug Administration of the United States of America and the Ministry of Health and Family Welfare of the Republic of India on co-operation in the field of medical products. Available at: http://www.fda.gov/downloads/InternationalPrograms/Agreements/MemorandaofUnderstanding/UCM385494.pdf. Accessed March 28, 2014.

9. FDA. Generic Drug User Fee Amendments of 2012. Available at: http://www.gpo.gov/fdsys/pkg/BILLS-112s3187enr/pdf/BILLS-112s3187enr.pdf. Accessed March 28, 2014.

10. FDA. Guidance for industry: ANDA submissions—refuse-to-receive standards. Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM370352.pdf. Accessed March 28, 2014.

11. Supplemental applications proposing labeling changes for approved drugs and biological products. Federal Register. 2013;78(219):67985–67999. Accessed March 28, 2014.  [PubMed]

12. Generic Pharmaceutical Association. Comments on generic labeling rule by GPhA and other groups.Available at: http://www.gphaonline.org/media/cms/Supply_Chain_Sign_On_Letter_to_FDA_on_Labeling_FINAL.pdf. Accessed March 28, 2014.

13. Public Citizen. Comments on proposed rule: “Supplemental Applications Proposing Labeling Changes for Approved Drugs and Biological Products”. Available at: http://www.citizen.org/documents/Comments%20on%20NPRM%203-12-14.pdf. Accessed March 28, 2014.

14. Towfic F, Fund JM, Fowler KD, et al. Comparing the biological impact of glatiramer acetate with the biological impact of a generic. PLOS ONE. 2014 Jan 8; doi: 10.1371/journal.pone.008375. Available at: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0083757. Accessed March 28, 2014. [PMC free article]  [PubMed] [Cross Ref]

15. FDA. Sandoz Incorporated 11/18/11: warning letter. Available at: http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2011/ucm314931.htm. Accessed March 28, 2014.

The Pharmaceutical Industry Tussles Over Biosimilars

P&T Journal
April 2014 - for a PDF copy of the published version go HERE.


Calling it a "biosimilar brawl" would be overstating the fireworks, which were exclusively verbal, and even there lacking in venom. But sitting two seats away from one another at a Federal Trade Commission (FTC) workshop on February 5, 2014, two biotech executives named Bruce Leicher and Geoffrey Eich sparred, a little heatedly, over the issue of whether pharmacists should have to notify physicians when pharmacists substitute an interchangeable biosimilar for the innovator biologic.

Notification is a big and controversial issue as the Food and Drug Administration (FDA) gets ready to approve the first biosimilars to be sold in the U.S. Congressional legislation allowing the FDA to consider biosimilars via abbreviated applications was passed as part of the Affordable Care Act ((FDA). That was four years ago. Since then, the FDA has slowly been publishing draft guidances on what it would be looking for from companies using this new abbreviated approval pathway. The Biologics Price Competition and Innovation Act (BPCIA) did not address notification. That is up to individual states under pharmacy practice statutes. But states are not waiting for the FDA to approve the first biosimilars before establishing laws on notification. The potential ipediments to patient access posed by some of those laws worry biosimilar suporters, including the Federal Trade Commission.

Small, struggling biotech companies such as Momenta Pharmaceuticals, Inc. oppose notification. Leicher, J.D., is senior vice president and general counsel at Momenta, which lost $108 million in 2013 and has two biosimilars in development, one in conjunction with Baxter.

Large branded companies, some with patented biologics such as Amgen, support notification. Eich is executive director, R&D policy, Amgen, Inc. which earned a tad over $5 billion in 2013 on, among other products, branded biologics such as Aranesp^® (darbepoetin alfa), Enbrel^® (etanercept) and Epogen^® (epoetin alfa).

Leicher argues that Amgen and allies such as Novartis/Sandoz, Hospira, Actavis, Boehringer, AbbVie, Genentech, and Lilly are pushing notification at the state level so that they will have "a forum for disparaging comments which can be made without the risk of enforcement." Even though some of those companies also market biosimilars--Hospira's erythropoietin (EPO) biosimilar called Retacrit^™ is a big seller in Europe, for example--Leicher says they are fine with notification because they have large sales and marketing arms which reach deep into physicians' offices.

Eich retorts that passing biosimilars off as generics is "increasingly disparaged by academia, regulators and competitors as misleading. They have to be foisted on patients switched at a pharmacy before administration." Biosimilars are not exact copies of biologics. They cannot be, given the way biologics are made, in cell cultures, using a much different and variable manufacturing process than the more precise, cookbook method for making generic copies of small molecule drugs. But biosimilars are generics in a general, conceptual sort of way.

Biosimilar issues also split pharmacists. "Naming" is one of the divides. The BPCIA did not specify how biosimilars should be identified for purposes of tracking and adverse reaction reporting. This is an issue the FDA will settle, not the states. In Europe, where biosimilars have been legal and sold since 2006, companies identify a product using the International Non-proprietary Name (INN), with both innovator and biosimilar products using the same INN, sans a suffix. The American Pharmacists Association (APhA) is dead set against using suffixes such as Greek letters (e.g. "alpha")  to denote the nonproprietary name of a biosimilar.

The American Society of Health-System Pharmacists (ASHP) thinks that normally it would be enough to attach the National Drug Code to the INN. That would be suffix enough. But the NDC identifier may not currently be used to track a product in all settings and other challenges such as the reuse of NDC numbers by manufacturers may make this approach currently difficult. "Therefore, we do not oppose the addition of suffixes to the INN name if experts believe this approach is needed to facilitate pharmacovigilance," says Christopher Topoleski, director, federal regulatory affairs, ASHP.

Chose any of the controversial biosimilar issues; pharmacists are invariably on the firing line. And some already feel they are dodging metaphorical bullets. First, the push for post-dispensing notification implies that pharmacists are somehow junior, physician-subservient partners in the patient pharmaceutical chain, even though prescription drugs are their fulltime business. Marissa Schlaifer, M.S., R.Ph., head of policy for CVS Caremark, calls notification "somewhat demeaning" to pharmacists. However, the act of notification won't be that big a deal. To the extent biosimilars are infused in physician's offices, pharmacists are out of the loop. Biosimilars will be provided in hospital clinics, too, obviously. But there pharmacists will have access to electronic medical records and an easy link to the physician. Retail pharmacists will have the biggest challenge if they have to call or FAX a physician to note a substitution.

The FTC held the panel on biosimilars to explore whether emerging state laws on biosimilars presented barriers to their use. Any roadblocks could be considered anticompetitive, giving the FTC the authority to intervene. Some states have already passed laws on that. So any state law is premature, a point made by California Governor Jerry Brown when he vetoed a bill in 2013 passed with strong bipartisan support by the California legislature. 

But biosimilars will be approved by the FDA probably within the next few years, making state laws on notification a very hot topic. Companies like Amgen, Novartis and Sandoz are on record backing pharmacist notification whenever a pharmacist substitutes either a different patented biologic or a biosimilar for the biologic the physician prescribed. The notification requirement would stay in place until a given state established an interoperable health records system. 

Two Categories of Biosimilars: Interchangeable or Not

The BPCIA anticipated that the FDA would grant abbreviated approval to biosimilars in two categories: those that are interchangeable with the patented (called "reference") product, and those that are not, which will be referred to as "highly similar." The FDA would first qualify a product as a biosimilar, meaning highly similar. A product deemed biosimilar could still differ in terms of inactive ingredients, purification processes, and other areas that are proprietary. Therefore, a product that achieves only biosimilarity will not be considered a therapeutic equivalent and will not be eligible for direct substitution without prescriber notification and approval.

The BPCIA allows the FDA to declare a biosimilar interchangeable--thereby substitutable without a physician's consent-- if two conditions are met. The biosimilar has to be expected to produce the same clinical result in any given patient and the risk in terms of safety or diminished efficacy cannot be greater for a switch from a patented to biosimilar than continued use of the innovator drug, where the drug is used more than once by the same patient. "The is a pretty high standard," says Phil Katz, a partner with the global law firm Hogan Lovells. "It is not the same as for substitution of small molecule generic drugs."

The FDA published three draft guidance documents on biosimilars in March 2012. They provided some clarity in terms of some of the methods the agency would use to sort through applications. But specificity on key issues such as how biosimilars would be named, standards for interchangeability and some other areas was sorely lacking. Those guidance documents have not been finalized. The FDA says it will publish four more draft guidances in 2014, including one on interchangeability. Marie A. Vodicka, regulatory affairs director, Hogan Lovells, says the FDA does not have to finalize guidance before it can approve a biosimilar application.

Kris Kelly, an FDA spokeswoman, says the FDA's Center for Drug Evaluation and Research continues to meet with sponsors interested in developing biosimilar products.  As of January 30, 2014, CDER had received 62 meeting requests for an initial meeting to discuss biosimilar development programs for 13 different reference products and held 53 initial meetings with sponsors. To date, CDER has received 22 Investigational New Drug (INDs) applications for biosimilar development programs, and additional development programs are proceeding under a pre-IND. Twenty-one biologics with a market value of over $50 billion will lose patent protection by 2019 in the U.S. alone.

While notification was the most controversial issue discussed at the FTC's February workshop, it wasn't the only one. The daylong discussion ranged over a number of topics, such as how state laws on small-molecule generics had affected uptake of those drugs, how biosimilars should be "named" and the associated issue of pharmacovigilance, meaning the tracking of adverse effects, as well as interchangeability.

Europe Way Ahead

Given the high cost of most biologics, the potential for lower prices and the availability of biosimilars in Europe and Asia, there is considerable pressure on the FDA to open the biosimilar floodgates. The European Union approved the first biosimilar, Omnitrope (somatropin), in 2006. To date, the European Medicines Agency (EMA) has approved 20 biosimilars within the product classes of human growth hormone, granulocyte colony-stimulating factor, erythropoietin and TNF. Once the EMA approves a product, it is up to an individual country whether to allow sales within its border. In June 2013, the EMA approved the first  monoclonal antibody (mAb) therapies for Johnson & Johnson’s Remicade (infliximab).  Those are Hospira's Inflectra and Celltrion's Remsima.  Sandoz's Zarzio® (filgrastim) has become the first biosimilar to overtake both its reference product (Amgen’s Neupogen®) and European market leader (Chugai’s Granocyte®).

Eight of the ten highest-expenditure Medicare Part B drugs in 2010 were biologics. Leigh Purvis, senior strategic policy advisor, AARP, the seniors' lobby, says the average annual cost of a branded biologic is around $34,550. Costs can run as low as $25,000 and as high as $200,000. Many of these biologics are infused in a physician's office. Where a senior under Medicare Part B receives that drug, he or she is responsible for a 20 percent co-payment. If that drug is procured under Part D, the Medicare out-patient drug program, there is a cap of $4550 for the patient. With regard to non-seniors, ACA marketplace plans typically put these expensive biologics on high tiers, where there is substantial cost sharing, although there, too, like with Part D, caps do come into play.

Express-Scripts looked at the 11 branded biologics which will lose patent protection over the next decade. Its back-of-the-envelope calculation is that an average 30 percent price discount for the biosimilar could yield a quarter of a trillion dollars of savings in the U.S. for those 11 products during the next decade. That is assuming no interchangeability until 2020.

Are States Jumping the Gun?

State laws mandating pharmacist notification or limiting interchangeability could crimp savings to individuals, employers and federal health plans Medicare and Medicaid. The FTC's position is that state laws aiming to protect patient safety can restrict the use of biosimilars, but those restrictions should be no broader than necessary to protect legitimate concerns. At the workshop, FTC Chair Edith Ramirez said, "There is substantial uncertainty at the state level surrounding how follow-on biologics will compete with their reference products." Last year, 15 state legislatures considered laws which would affect how interchangeable biosimilars could be dispensed by pharmacists. 

Jessica Mazer, assistant vice president of state affairs for the Pharmaceutical Care Management Association, says the most radical state bill--the PCMA opposes state limitations on prescribing of interchangeables--was in North Dakota. It enacted a law that requires a pharmacist to notify a prescriber within 24 hours of substitution. Some states are including provisions allowing substitutions only where a state has some measure of interoperable electronic health information exchange. Another state legislative permutation is the walling off of some drug categories from interchange, particularly insulin products.

Some of the panelists at the FTC workshop besides Leichner had sharp criticism of the Amgen/Novartis/Hospira, etc.  proposal which Sumant Ramachandra, M.D., Ph.D., M.B.A., senior vice president and chief scientific officer of Hospira, Inc., justified on the basis of "transparency." 

Amgen's Eich explains, "Absent some level of interoperable health records or after the fact communication between pharmacy and clinician's office, the patient's medical record will be rendered either ambiguous or inaccurate."

Momenta's Leicher says that e-prescribing networks are operational nationally, and physicians already have the capability to reach down to the pharmacy and find out whatever it is they want to know about a patient and his or her prescriptions. Steven B. Miller, M.D., M.B.A., senior vice president and chief medical officer for Express Scripts, Inc., agrees. He points out that SureScripts, on whose board of directors he sits, reaches 500,000 physicians, 65,000 pharmacies and all 5500 hospitals in the U.S. "We already have a system that is safe and effective," he insists. "Notification is truly unnecessary."   

Miller distinguishes that current system with an interoperable system, which is nowhere in sight. He said physician offices, hospitals and pharmacies have about 30 different e-prescribing software systems, and that complexity was made worse by the 2009 economic stimulus bill which contained about $19 billion in grants for physicians and hospitals to get software in place. "The current system is immature," he explains. "Some software cannot even express the formulary a patient is on. Interoperability is a fantasy, and we won't have it for a long, long time."

Even some proponents of notification admit the proposal they support has some weaknesses. Mark McCormish, M.D., Ph.D., global head, biopharmaceutical development, Sandoz, admits, "We have tried to come up with language, not that it is perfect or great."   

What is in a Name?

How biosimilars should be named is also the subject of substantial controversy. It is an important issue because a physician or pharmacist reporting an adverse reaction to a national health agency or the manufacturer needs to be able to distinguish the offending drug from others in its class, both branded and biosimilar. In an effort to influence the FDA's position on naming, the Generic Pharmaceutical Association (GPhA) submitted a petition to the FDA in 2013 requesting the FDA implement its International Non-proprietary Name (INN) policy equally to all biologics. The World Health Organization administers the INN system. An INN names the active ingredient, such that products that share the same INN can be readily identified as sharing the same active ingredient. In addition to the INN, a product (including biosimilars) will have other names and identifiers; for example, a brand name and in the U.S. an NDC which readily distinguish it from other products that share the same INN. The EU has used INNs to track biosimilars (and brand-name biologics) as part of pharmacovigilance programs.

Underlining how divided the pharmaceutical industry is over multiple biosimilar issues, Novartis, Amgen's ally on notification, supports the GPhA's position. Amgen opposes it.

The BPCIA doesn't address how biosimilars should be named. It was a subject which came up during congressional debate but no provision was added to the bill. The FDA outlined its naming position for biosimilars in a policy paper sent to the WHO in 2006, in support of the current WHO naming conventions. The GPhA's petition states that in its 2006 paper the FDA  "agrees that there should be no change in global policy and rejects distinctive INN designations for biosimilars."

In a response to the GPhA petition, Paul R. Eisenberg, M.D., M.P.H., F.A.C.P., F.A.C.C., senior vice president, global regulatory affairs and safety, Amgen Inc., says the GPhA cites only a portion of the FDA's 2006 policy paper, but omits the remainder of the context.  "We believe that the best solution is that the reference product and biosimilar should share a root and have distinct suffix," he adds. Greek letters, such as alpha, beta, gamma, or the manufacture’s name could serve as the distinct suffix. Examples of the resulting name would be “supermab alpha” or “supermab Amgen.” This is similar to the naming convention employed by the Japanese regulatory authority, Eisenberg states.

The reason Amgen and others believe biosimilars deserve unique, non-proprietary names is that unlike chemically synthesized drug products, no two biological products are identical, and small differences can have significant and unpredictable effects on patients' immune responses. They also argue that the inability to disaggregate safety information could lead to significant safety risks.

But Alan M. Lotvin, M.D., executive vice president of specialty pharmacy for CVS Caremark, says a unique suffix, for example, would "confuse the role of the nonproprietary name." He argues that biosimilars approved in Europe and elsewhere have the same INN as their reference with no evidence of safety problems. Different nonproprietary names would discourage states from allowing substitution even if the FDA has designated the biosimilar as interchangeable. "The different nonproprietary name will be used to suggest that the active ingredient in the two medicines are different," he states.

            

The American Pharmacists Association (APhA) has also weighed in against the use of suffixes. Back during an FDA workshop on the first set of draft guidance in May 2012, Marcie Bough, PharmD, then senior director, government affairs with the APhA, said suffixes present challenges for pharmacy operating systems and in processing for fulfilling orders. Suffixes may not be included in the original electronic or written prescription. they may fall off the electronic drop down menu order form for product selection, and they many not fit into the data field in the database. Michelle Spinnler, an APhA spokeswoman, says that continues to be the group's position.

The ASHP also sees potential problems with suffixes, though it sees problems, too, with unique names. "Unique INNs would complicate the collection of product safety data across the industry," notes Topoleski. "Unique INNs would make U.S. product names different than those in the rest of the world and such a policy would be contrary to the World Health Organization naming system." The ASHP therefore wouldn't oppose suffixes such as Greek letters but it would oppose prefixes.

Patient groups are something a wildcard in the biosimilar debate. On the one hand, they want cheaper biosimilars. On the other hand, they want to be assured those interchangeable and highly similar biosimilars are as safe and effective as the reference drug, and right for the patient. Marcia Boyle, president and founder of the Immune Deficiency Foundation, wants the FDA to prohibit immunoglobulin therapies from being interchanged, at least until the science advances significantly. She bolsters her case by referring to the worldwide voluntary withdrawl in 2010 by

Octapharma USA Inc. of 31 lots of octagam® [Immune Globulin Intravenous (human)] 5% Liquid Preparation]. This was performed as a result of an increased number of reported

events. "Unlike generic drugs, biosimilars can never be identical copies of a reference

product," she states. "The choice of product should not be determined by a pharmacist, regulator, or insurer, but by a physician in consultation with his/her patient."

It is impossible to predict how the debates over notification, interchangeability, and naming will turn out. But given the overwhelming success of small-molecule generics since Hatch-Waxman was passed in 1984, it is hard to imagine that either the FDA or the states will substantially stymie biosimilar access.