Fdl122002

Dec. 20, 2002
THE FOOD & DRUG LETTER
Issue No. 666
Dec. 20, 2002
CLARITIN APPROVAL MARKS SIGNIFICANT SHIFT IN RX-TO-OTC SWITCHES
The switch of Schering-Plough’s Claritin to over-the-counter (OTC) status set new precedents whose implications will reach far beyond drugstore shelves and affect the pharmaceutical industry for years.
FDA’s Nov. 27 approval of OTC Claritin, the non-sedating antihistamine (loratadine) culminated an extraordinary odyssey through the regulatory system. The small tablet is at the confluence of powerful interests– drug companies, regulators, payers and consumers.
Previously one of the nation’s top-selling prescription drugs, Claritin is the latest in a number of prescrip- tion drugs that have switched to OTC status (see “Rx Drugs Switched to OTC,” Page 3). Some industryobservers have forecast a rising tide of Rx-to-OTC switches, and indeed a slew of drugs are reportedlywaiting in the wings to seek OTC status (see “Rx-to-OTC Switch Candidates,” Page 3).
Switching a product from prescription to OTC involves critical decisions for drug makers. A properly executed Rx-to-OTC switch can maximize a company’s revenue from a drug, and may provide an additionalbonus of exclusivity. But the transition to OTC is also fraught with risks and may not always be in the bestinterests of pharmaceutical companies or patients, experts say.
Opening Of OTC Floodgates Uncertain
Whether the OTC approval of Claritin heralds an opening of the floodgates remains to be seen. What’s clear is that the rules of the game are changing. In this issue, The Food & Drug Letter explores some of thelessons gleaned from the Claritin switch and examines key issues facing drug makers eyeing switches.
Claritin has been a success since its approval as a prescription-only drug in April 1993. One of the first of a new generation of antihistamines, Claritin is less likely to cause drowsiness than traditional antihista-mines based on diphenhydramine. Its safety profile offers important benefits for the 10 percent to 30 percentof adult Americans who suffer from seasonal allergy symptoms. Claritin generated $3.1 billion in salesannually for Schering-Plough. That figure represented almost one-third of the company’s revenue.
Other second-generation antihistamines include Aventis’ Allegra (fexofenadine) and Pfizer’s Zyrtec (certirizine).
On July 22, 1998, Wellpoint Health Networks petitioned the FDA to EDITOR’S NOTE: The
switch Claritin, Zyrtec and Allegra from prescription to OTC status. Formed in 1992 by Blue Cross of California’s managed care business, Wellpoint is not be published Jan. 2. Thenext issue will be Jan. 8.
(See OTC SWITCH, Page 2)
THE FOOD & DRUG LETTER
Dec. 20, 2002
OTC SWITCH, fromPage 1
without the consent of the drug company sponsor? one of the nation’s largest health insurers, provid- The definitive answer, according to some of the ing benefits for more than 40 million members.
nation’s top experts surveyed by The Food & DrugLetter: Maybe.
In its petition, Wellpoint argued that the second-generation antihistamines were safer and Switch Criteria
more effective than antihistamines currently soldOTC, and therefore do not meet the criteria for prescription status. The insurer said that consumers (FDCA), a drug is presumed available OTC unless want easy access to affordable healthcare and it has toxic effects, requires a doctor’s supervision, would prefer to use less expensive medications or there is some other compelling reason to protect that don’t require an office visit for a prescription.
the public health. For a drug to be sold OTC, apatient must be able to safely diagnose his or her condition, understand the drug regimen and use the Claritin or a generic, is in the best interest of drug appropriately without professional guidance.
allergy sufferers nationwide,” said Robert Also, the drug itself must not have any significant Seidman, Wellpoint’s chief pharmacy officer. “It lowers the cost and eases access. Any memberwho feels they need to consult with a physician can There are three ways that a prescription drug consult today just like they did yesterday.” Wellpoint’s interests also include financial The FDA can remove prescription restrictions considerations. The OTC switch of the third- if it determines they are not necessary to generation antihistamines is expected to save the protect public health and if it deems the drug company about $90 million – $45 million from safe and effective for self-medication.
prescription costs and $45 million for copays.
Any “interested person” – usually a drugsponsor – can file a supplemental new drug “Our responsibility, whether to an employer application (NDA) for an approved prescrip- group or an individual subscriber, is to provide broad access to pharmaceuticals in an affordable Any interested person who wants an Rx-to- manner,” said Seidman. “We’re going to take every OTC switch can file a citizen petition asking opportunity to encourage our members who have the FDA to consider changing a drug’s status.
chronic diseases to stay on their meds, to thinkabout gold standard generic drugs, and we’re going Wellpoint’s petition seeking the OTC switch to foster conversion of safe and effective drugs for Claritin, made under the third of the above from prescription to OTC status. It’s a complicated options, drew fire from Schering-Plough and other but complete strategy to protect the affordability of Wellpoint’s move took many in the pharma- ceutical industry by surprise. Never before had a Allergy Drugs Advisory Committees, which met payer group asked that a class of drugs be to consider the OTC switch of second-generation designated OTC. When such a request is filed antihistamines, Schering-Plough contended that with FDA, it is typically from a drug company switching Claritin to OTC would not be in the that also provides scientific data to back up the best interest of patients. Changing the prescrip- claim that the product is safe for OTC use as tion status of Claritin would force patients to labeled – none of which Wellpoint submittedwith its petition.
(See OTC SWITCH, Page 4)
Dec. 20, 2002
THE FOOD & DRUG LETTER
Rx DRUGS SWITCHED TO OTC
Rx-TO-OTC SWITCH CANDIDATES
Nasonex (mometasone furoate monohydrate) Schering-Plough THE FOOD & DRUG LETTER
Dec. 20, 2002
OTC SWITCH, fromPage 2
received. However, the FDA is unlikely to take suchdramatic unilateral action, agency officials said.
diagnose themselves, self-treat and pay theentire cost of their allergy medications.
“There is something in the law that if a drug can be sold without a prescription, it should be,” “We believe that prescription status of these said David Hilfiker, project manager in the Drug medications is necessary to protect and optimize Center’s Division of Over-the-Counter Products.
public health,” Robert Spiegel, the company’s “We traditionally haven’t put ourselves in the chief medical officer, told the committees.
position to force a company to take a drug [OTC].” Other drug company officials also tried to Pharmaceutical Research and Manufacturers poke holes in Wellpoint’s arguments. Francois Nader, senior vice president for North American Wellpoint petition and the strategy of switching by fiat.
medical and regulatory affairs at Aventis, said thatwhile Wellpoint described sedating antihistamines “We believe that’s inappropriate,” said spokes- as “dangerous,” the insurer’s own formulary man Jeff Trewhitt. “FDA should take a drug over the reserved the second-generation antihistamines for counter only in active collaboration with the sponsor- patients “who have failed or are unable to tolerate ing company. It’s the company that took this through the 12-15-year drug approval process, generating anNDA with as many as 100,000 pages of scientific Schering-Plough and Aventis also argued that data. They truly know the medicine best.” improper use of OTC second-generation antihista-mines could lead to health problems by masking If Wellpoint succeeds, observers have forecast serious illness, since sniffling and sneezing could a flood of citizen petitions requesting OTC switch- be symptoms of asthma or other conditions. Among ing for a range of drugs, including those for asthma, others that opposed the switch was the National diabetes, osteoporosis, oral herpes infection and Consumers League, which contended that the OTC switch would eliminate an entire class ofnonsedating antihistamines. Making the drugs OTC Wellpoint has no plans to target any other would reduce consumers’ choice to self-medica- drugs. “There aren’t any other easy home-run hits,” tion with less expensive sedating drugs, putting them in danger of accidents. Others against theswitch were: However, the insurer has asked that Schering- Plough’s therapeutic follow-up to Claritin, Clarinex ! The American Academy of Asthma, Allergy (desloratadine), also be switched to OTC status.
! The American Academy of Otolaryngic Allergy Battles Against Generics
! The patient advocacy group Asthma Network/ Claritin, whose patent expired Dec. 19. A growing By a vote of 19 to 4, the committee over- list of competitors announced plans to launch generic versions of loratadine, and the new Allegra, Claritin and Zyrtec. More than a year Clarinex was meant to lay claim to the market later, the FDA, which usually follows the recom- mendations of its advisory committees, still has notissued a decision on the Wellpoint petition.
But the Clarinex launch was delayed by an FDA investigation into Schering-Plough’s manufacturing In theory, the agency could grant Wellpoint’s petition based on safety and efficacy data already (See OTC SWITCH, Page 5)
Dec. 20, 2002
THE FOOD & DRUG LETTER
OTC SWITCH, fromPage 4
mine market. The absence of drowsiness andcholinergic effects are powerful selling points that practices, leaving the door open for generic competi- experts have said will give diphenhydramine- tors to win over Claritin users before the brand maker based antihistamines a run for their money.
could convert them to Clarinex, which was finallyapproved in February 2002.
OTC Claritin enjoyed a full 10 days of market exclusivity after its introduction Dec. 10 before Potential generic competitors got a jump on generic competitors hit the market. Wyeth received Claritin several years before its patent expiration.
tentative approval for the ANDA on its version of Geneva filed an abbreviated new drug application loratadine, which will be sold as Alavert and could hit the shelves by the end of December.
Schering’s patents were unenforceable. Four othergeneric manufacturers submitted ANDAs for Wyeth also plans to launch its version of loratadine in 1999, three in 2000 and five the follow- Claritin-D (loratadine/pseudoephedrine sul- ing year, including McNeil Consumer Health Care. In fate) in 12-hour and 24-hour formulations in 2001, Whitehall-Robbins, now Wyeth, filed an early 2003. Novartis also has a loratadine ANDA for its version of loratadine, also contending version waiting in the wings and generic maker Schering’s patents were invalid and unenforceable.
Andrx is considering selling the drug in theprivate label market.
By mid-2002, Schering-Plough had launched 15 lawsuits against generic companies to defend its Competitive Market Expected
loratadine patents, and lost key rounds in court.
Clarinex gave Schering-Plough a foothold in market will be flooded with loratadine products both the OTC and prescription markets for second- starting in early 2003. Competition from generic generation antihistamines. “The approval of versions of loratadine is expected to drive the Clarinex provided us with the opportunity to move price from the prescription rate of more than $2 Claritin to the OTC category while still maintain- per pill down to about $1 per pill, comparable ing a presence in the prescription field,” said to currently available OTC antihistamines.
company spokesman William O’Donnell.
Health insurers are expected to drop coverage Faced with a losing battle, Schering-Plough for second-generation OTC antihistamines.
capitulated and filed its own supplemental NDA Wellpoint already has. Aetna, the nation’s second- to switch Claritin to OTC March 8, 2002. After largest health insurer, said it will no longer cover contending that OTC Claritin posed a risk to the Allegra, Claritin or Zyrtec unless a doctor makes a public health before the FDA’s advisory commit- special request. Several other insurers have tees the previous year, the company switched gears and made the case that the drug was safe touse OTC when directed by the label.
According to industry sources, health plans intend to encourage a trial of OTC loratadine by The FDA approved all five formulations of making sure patients’ out-of-pocket copayment for Claritin for OTC sale for allergic rhinitis. Based on Rx versions plus the physician office copay is not additional data provided by the company, FDA appreciably less than the amount they pay for OTC subsequently approved Claritin for the OTC treatment of chronic idiopathic urticaria. However, Schering isfar from alone in the market for OTC antihistamines.
Other drug companies also are closely watch- ing the Wellpoint petition as they maneuver the Rx- Industry observers expect the introduction of OTC loratadine to shake up the consumer antihista- (See OTC SWITCH, Page 6)
THE FOOD & DRUG LETTER
Dec. 20, 2002
OTC SWITCH, fromPage 5
would be the only OTC drug available at prescrip-tion strength for the prevention of heartburn.
to-OTC switch for their products. One drug in asituation similar to Claritin is AstraZeneca’s Several companies are champing at the bit to get Prilosec (omeprazole), one of a new generation of OTC approval for cholesterol-lowering statin drugs, proton pump inhibitors that treat gastroesophageal a huge potential market. In July 2000, an FDA advi- reflux and ulcers. Prilosec’s move to OTC will sory committee rejected OTC switch applications for follow a similar shift for the earlier generation of Merck’s Mevacor (lovastatin) and Bristol-Myers H2 blockers that switched to OTC status in the Squibb’s Pravachol (pravastatin). The committee mid-1990s, including Tagamet (cimetidine) and asked for the firms to provide more studies to demon- strate the public’s ability to self-diagnose the need forstatin therapy, and to show that consumers can use the world for several years, Prilosec is key toAstraZeneca’s financial health. It generated $3.7 Merck is reportedly ready to try for approval billion in worldwide sales for the company, or again, and has formed a joint venture with Johnson nearly 35 percent of AstraZeneca’s revenues & Johnson for the OTC switch of Mevacor.
from continuing operations. AstraZeneca foundits patents challenged by generic-drug compa- One of the stumbling blocks to the OTC approval nies in theU.S. and Europe. Despite winning of statin drugs is the need to monitor serum choles- U.S. court challenges, five companies pounced terol and lipid levels, which involves office visits for with generic versions in the United Kingdom blood tests. Among the solutions being bandied about after a court overturned its omeprazole patent.
is for pharmacists to become more involved inmonitoring drug treatment, taking a greater role in the management of cholesterol-lowering and anticoagu- AstraZeneca sold OTC rights to Prilosec to Johnson lant therapy. Statins are among the candidates for a & Johnson in 1997. Both companies have declined to proposed third class of regulated drug, between disclose the details of their arrangement.
prescription and OTC (see related story, Page 9).
The FDA approved the first generic form of Dual Regulatory Status
omeprazole Nov. 4, giving the nod to an ANDAfrom KUDCO, the U.S. unit of Schwarz Pharma.
When a product goes OTC, the manufacturer KUDCO, the only firm to emerge from litigation typically discontinues its prescription counterpart.
with AstraZeneca with a valid patent for the drug, There are cases in which it makes more sense for a is marketing its version of omeprazole in agree- prescription version to remain available in certain ment with generic makers Genpharm and Andrx.
strengths or for certain indications. “Dual regula-tory status” refers to drugs with the same molecule With the patent noose tightening, AstraZeneca and the same brand name sold simultaneously in filed a supplemental NDA for an OTC version of Prilosec. A joint session of the FDA’s Nonpre-scription Drugs Advisory Committee and the Prescription drugs may differ from their OTC Gastroenterological Drugs Advisory Committee versions in strength, dosing, indication, packaging recommended the approval of OTC Prilosec June or other factors. Typically, OTC drugs are sold at a 21. Johnson & Johnson received an “approvable” lower dose than their prescription counterparts.
letter from the FDA Aug. 8, with a request for Dual regulatory status was the strategy used for products such as Imodium (loperamide) andPepcid (famotidine).
If fully approved, an OTC version of Prilosec is expected to be on the market by mid-2003. It (See OTC SWITCH, Page 7)
Dec. 20, 2002
THE FOOD & DRUG LETTER
OTC SWITCH, fromPage 6
patients can self-diagnose, according to saidregulatory strategist Thomas Blake, who has been involved in the Rx-to-OTC switches of such seeking dual regulatory status offers advantages and products as Acutrim (phenylpropanolamine), Gyne- disadvantages to drug companies. Dual regulatory Lotrimin and Lotrimin AF (clotrimazole) and status can extend patent protection and market exclu- Nicorette (nicotine polacrilex). “Theoretically, sivity while taking full advantage of brand recognition most prescription drugs can be switched,” he said.
created by direct-to-consumer advertising.
In the case of antacids, companies are better With dual status, however, companies risk spread- served by avoiding an indication such as duode- ing their resources too thin over different markets. “Do nal ulcer or gastroesophageal reflux, which a you want to be competing against both prescription and patient is not able to recognize, and sticking to OTC products?” asked Richard Tinsley of the pharma easy-to-understand signs and symptoms such as consulting firm Putnam and Associates.
heartburn. “You don’t really switch a drug, youswitch the labeling,” Blake said.
Thus, for financial as well as regulatory reasons, industry experts advise that drug makers should consider carefully whether it is worth it to prescription restrictions on topical antifungals for the treatment of vaginal yeast infection wasthat women may not be able to accurately To Go OTC Or Not
diagnose their condition and may not recognizethe signs of other serious pelvic disease.
usually been on the prescription market for at appropriate health care or mask the symptoms least five years and have been taken by large “There’s a certain amount of time we like to infection drugs, we had concerns that using the see prescription products on the market, to get a drug would mask the symptoms of something level of comfort with the safety reporting experi- else,” said Blake. “We did a ton of research to ence as a prescription product,” said the Drug show that the itch of candidiasis is not dupli- (See OTC SWITCH, Page 8)
The FDA considers a number of factors in an Rx-to-OTC switch to determine whether consumers Timetable for OTC Switches
can use a drug safely. The safety of a drug when usedin an OTC setting is a complex issue involving far Development Step
more than the toxicity of the compound itself.
“We look at whether the condition that the product is intended to be used for can be perceived by consumers, whether they recognize that they indeed have that condition and no other,” Hilfiker said. “We want to make sure there won’t be any harm come to the consumer as a result of misdiag- nosis of their condition or use of the product.” The secret to a successful OTC switch is to make the indications and labeling sufficiently clear so that THE FOOD & DRUG LETTER
Dec. 20, 2002
OTC SWITCH, fromPage 7
uct backed by the momentum of brand identity inthe OTC setting. There are cases, however, in cated by the other vaginal infections, so the label which a company chooses not to take the OTC was geared toward that indication. And just to route, for whatever reason. As the Wellpoint be sure, we put on the label for the new OTC case illustrates, other companies may find drug that if you don’t see relief in three days, see themselves in a situation similar to Pfizer, The process of switching a drug to OTC can Avoiding the Switch
take years, and should begin early in the product’slife cycle (see “Timetable for OTC Switches,” According to industry experts, drug companies Page 7). Preparations for the switch include label can employ a number of strategies to delay or comprehension studies in which subjects are tested derail efforts to take product OTC against the on their ability to read a product label and explain their intent to follow specific label instructions.
“You present the label to the consumer and ask ! Health care attorney Susan Burke suggests that them questions about it,” explained Hilfiker. “You drug makers develop their marketing efforts refine the label until it’s something you’re confi- with an eye towards OTC implications.
Pharmaceutical companies should review theirmarketing and advertising materials to make An in-use study may be required to deter- sure the health insurer’s position in favor of mine consumer usage patterns, including compli- self-diagnosis and self-medication is not ance with dosage directions, concurrent use of supported. Marketing materials should give a OTC and prescription drugs, effectiveness and prominent role to the doctor and reenforce the the occurrence of rare side effects. In an in-use importance of his diagnosis and care.
study, patients are presented with a drug andasked to determine whether it’s appropriate for ! Drug makers should foster contacts with physi- them, then given the drug, sent home and told to cian, medical and consumer groups that oppose use it according to the label. “We look for use OTC switches without the manufacturers’ patterns, whether consumers use it appropriately consent. The more grassroots consumer support or run into any problems when trying to follow for keeping a prescription status, the less likely the label instructions,” said Hilfiker.
the FDA is to buy the insurer’s claim that it iswidening consumers’ access to effective and affordable drugs, according to Burke.
products to OTC, it’s important for them to appre-ciate the ethical, marketing and clinical challenges ! Firms can find a scientific issue that will posed by the nonprescription market.
give the FDA pause, Blake suggests.
“Dredge safety data that may show a differ- “Bottom line, when you make a drug over ent light on the product,” Blake said. This the counter, you have to find ways to take the place of the physician,” said Blake. “With prescription drugs, you have the physician nonsedating antihistamines. Aventis argued buffer, so the drugs can be more toxic and have monitoring built in. The challenge to the industry unintended health and safety consequences, is taking the place of the physician. That is a still undergoing post-approval safety andeffectiveness trials and post-marketing Taking a drug over the counter often makes good sense, particularly for an innovative prod- (See OTC SWITCH, Page 10)
Dec. 20, 2002
THE FOOD & DRUG LETTER
REGULATORS CONTINUE TO EYE
counter grew in the 1990s. The matter was ad-dressed again by a 1995 report by the General POSSIBLE THIRD CLASS OF DRUGS
When the topic of switching drugs from prescrip- tion to over-the-counter (OTC) comes up, the idea of “Other countries’ experiences do not support a creating a third class of FDA-regulated drugs be- fundamental change in the drug distribution of the tween prescription and OTC often accompanies it.
U. S., such as creating an intermediate class ofdrugs,” the GAO report said. “The evidence that While the U.S. has traditionally used a two- does exist tends to undermine the contention that tiered system, a third class exists in many other major benefits are being obtained in countries with western nations, including Canada and Europe.
A third class for drugs “is certainly something The prospect for a third class of drugs next arose that has been talked about a lot at recent meetings,” in 2000 during FDA public hearings on OTC said David Hilfiker, advisory project manager in switches. Proponents of a three-tier system argue that the Drug Center’s Division of OTC Drug Products.
the third class could facilitate the OTC transition of “The interest is to possibly creating new opportu- drugs, such as cholesterol-lowering statins, several of nities for converting additional drug categories to which are in line for nonprescription status. A major something other than prescription, such as choles- obstacle to approval of OTC statins is patients’ inability to self-diagnose their cardiovascular healthand monitor the course of therapy. Regular visits to a The proposal for a third class of drug under FDA doctor are necessary for monitoring and blood tests.
purview was first raised in 1974. The third classwould cover drugs available without a prescription, Statins As Third Class Candidates
but only through a pharmacist, similar to the Canadianand European systems. Drugs in the third class would The third class has strong support within the not be sold in other retail stores, convenience stores pharmacy community, which has long advocated a or supermarkets that lack a pharmacy.
more central role for the pharmacist in the healthmanagement of patients, particularly in chronic Competition Concerns
disease areas such as diabetes, high blood pres-sure, asthma and high cholesterol.
Although several medical groups supported the proposal, the U.S. Department of Justice Lining up against a third class of drugs are objected that a third class would restrict competi- Pharmaceutical Research and Manufacturers of tion, limit consumer availability and choice, and Products Association (CHPA), the AmericanMedical Association (AMA) and a long list of FDA analysis of the issue revealed that “no controlled studies or other adequate research datahave been supplied to support the position that any While the issue isn’t dead, it is unlikely that the class of OTC drugs must be dispensed only by FDA will move to a three-class system any time soon.
pharmacists to ensure their safe use.” The agencyconcluded, “There is at this time no public healthconcern that would justify the creation of a third “It’s being discussed and considered still, class of drugs to be dispensed only by a pharmacist but there are issues that are making us pause,” said Hilfiker. “There are logistical consider-ations, and the entire health care industry would The issue regained currency as the number of have to invest a considerable amount of money formerly prescription products going over-the- THE FOOD & DRUG LETTER
Dec. 20, 2002
OTC SWITCH, from Page 8
associated with self-diagnosis and self-treatmentof asthma, and some potential for misuse of the product, the benefits of easy availability to con- quested the assessment of unanticipatedadverse reactions in pediatric patients, and In addition, the agency suggested that labels had also asked that electrocardiographs be for the inhalers warn that the product should be used only after a physician diagnoses asthma.
The FDA’s Pulmonary-Allergy Drugs Advi- ! When all else fails, firms can stall, Blake sory Committee discussed the switch at a public recommends. “If a company doesn’t want to meeting in May 1983. After lengthy debate switch a drug, the way you handle it is by among committee members, invited experts and dragging your feet,” he said. “The onus is on the public, the panel recommended that FDA the company to create labeling. It may take a rescind its proposal to make metaproterenol a week or it may take 10 years. The ball is nonprescription drug, which the agency did a And even when a decision to make the switch has been reached, the transition from Rx to OTC when the agency was considering Hoechst’s status will not necessarily be smooth.
nonsedating antihistamine Seldane (terfenadine) forOTC status. Approved on a prescription basis in 1985, Seldane appeared safe when used alone but switch was in October 1982, when it proposed was associated with potentially fatal cardiac OTC availability for the bronchodilator Alupent arrhythmia when taken with certain other drugs.
(metaproterenol) in a metered-dose inhalationaerosol for asthmatics. The agency’s proposal – Hoechst, now Aventis, developed a related formulated without input from an advisory commit- compound, Allegra (fexofenadine), which pro- tee, drug companies or the public – met with vides the same benefits of terfenadine without the risk of arrhythmia. Allegra was approved asa prescription drug in 1997, and the following year all products containing terfenadine were claimed that improper use of metaproterenol voluntarily withdrawn from the market. Now inhalers could harm young children. The FDA’s Allegra is among the products on deck for an position was that while there were some risks Cynthia Carter
Annette Licitra
Susan Cunningham
Elizabeth Tilley-Hinkle
J.T. Hroncich
Bruce Goldfarb
Copyright 2002 by Washington Business Information, Inc. All rights reserved. The Food & Drug Letter (ISSN 0362-6466), an in-depth analysis of regulations
and issues affecting the pharmaceutical and biologics industries, is published biweekly, 24 issues, for $1,095 per year. Photocopying or reproducing in any form,
including electronic or facsimile transmission, scanning or electronic storage is a violation of federal copyright law and is strictly prohibited without the
publisher’s express written permission. Subscribers registered with the Copyright Clearance Center (CCC) may reproduce articles for internal use only. For
more information, contact CCC at www.copyright.com or call (978) 750-8400.

Source: http://brucegoldfarb.com/FDL3.pdf