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WASHINGTON--(BUSINESS WIRE)--Biotechnology Industry Organization (BIO) President and CEO Jim Greenwood released the following statement regarding the Congressional Budget Office (CBO) report issued today projecting cost savings from S. 1695, the Biologics Price Competition and Innovation Act of 2007:
"The CBO report shows that developing a pathway to review and approve follow-on biologics will result in cost savings to public and private purchasers of biologic products over a ten year period. The report finds that most of the savings will be obtained several years after a follow-on pathway is established, reinforcing the need for Congress to develop and pass a responsible pathway this year that protects patient safety and preserves innovation. We are essentially leaving money on the table the longer we wait to implement a pathway.
"By relying on the provisions in S. 1695, the CBO study also shows that we can achieve meaningful cost savings in biologics spending while providing needed protections to allow for continued innovation. H.R. 1956, the Patient Protection and Innovative Biologic Medicines Act of 2007; H.R. 5629, the Pathway for Biosimilars Act; and S. 1695 all come close to striking this necessary balance.
"Notably, the CBO study projects savings in-line with the estimates from the studies we, unlike others, have continued to reference, including those conducted by Avalere Health and by a research team led by Professor Henry Grabowski of Duke University.
"While follow-on biologics will provide real savings in the aggregate to the government and consumers, the estimated savings will constitute 0.065% of total healthcare spending over the next ten years. Therefore, Congress must ensure proper incentives for continued biomedical innovation in any follow-on biologics pathway so that we don't achieve relatively minor savings as a percentage of overall health care spending at the cost of continued innovation.
"BIO will continue to encourage the House and Senate to consider and pass legislation to create a pathway for the approval of follow-on biologics which protects patient safety and provides incentives for continued innovation.
The CBO cost estimate is available at:
http://www.cbo.gov/ftpdocs/94xx/doc9496/s1695.pdf.
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The Congressional Budget Office (CBO) today released a cost analysis finding that the creation of an abbreviated pathway for follow-on biologics -- or biogenerics -- would save the federal government $6.6 billion over ten years and lower total expenditures for biologics by $25 billion over the same time period.
"For a quarter century, generic versions of chemical drugs have saved consumers and payors billions of dollars. Now, CBO has confirmed that giving FDA additional authority to approve generic versions of biologics will save billions more," said PCMA President and CEO Mark Merritt. "Even greater savings would be available if Congress simply applied to biologics the Hatch-Waxman standards that are currently used to approve generics for chemical compounds. It would be helpful if some provisions in the bill -- such as 'evergreening' -- which unnecessarily delay the entry of biogenerics were reconsidered. CBO acknowledges that the 'evergreening' issue will present significant problems beyond the ten-year scoring window."
CBO estimates that:
Unlike conventional drugs, there is no clear regulatory process where biogenerics can be approved by the FDA. PCMA was joined by a number of influential consumer, employer, and insurer groups who endorsed the "Access to Life Saving Medicine Act of 2007," bipartisan legislation that seeks to create a clear regulatory pathway for biogenerics.
PCMA is the national association representing America's pharmacy benefit managers (PBMs), which administer prescription drug plans for more than 210 million Americans with health coverage provided through Fortune 500 employers, health insurance plans, labor unions, and Medicare Part D.
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Cambridge-based Genzyme Corp. has developed a portfolio of life-saving medications to treat a number of rare illnesses, such as Pompe disease and Gaucher's disease. But the drugs come at a steep price: $200,000 to $300,000 a year.
In a bid to control the soaring costs of drugs, Congress is edging closer to approving a formal process to let generic drug makers market knockoffs of advanced biologic drugs, such as those made by Genzyme. Biologics are made from living organisms instead of chemicals. Europe has already approved several biogenerics - also called "biosimilars" or "follow on biologics."
"The train is leaving the station," said Barry Karger, director of the Barnett Institute at Northeastern University, which is hosting a workshop today and tomorrow to help more than 100 industry leaders prepare for the coming wave of biogenerics in the United States.
"It's happened in Europe. It's happening in Canada. And it's going to happen in the US," he said.
Whenever it happens, it's likely to have a major impact on Massachusetts, which is home to one of the largest biotechnology clusters in the world.
Drug makers like Genzyme and Biogen Idec Inc. could potentially lose billions of dollars to generic competitors. And at least one Massachusetts company, Momenta Pharmaceuticals Inc., of Cambridge, hopes to cash in on the trend by helping to develop some of the biogenerics.
In addition, health insurers and advocates are counting on legislation to help rein in drug prices and the soaring cost of healthcare. Generic biologics are expected to cost 10 to 30 percent less than traditional biotech drugs.
But the issue is hardly clear-cut. Generic versions of traditional "small molecule" drugs have been around for decades, but industry officials say it's nearly impossible to produce an exact replica of a more complex biologic.
Biotech companies sometimes have trouble replicating even their own drugs when they build new plants or change production processes.
Genzyme Corp., for instance, has struggled for months to persuade the Food and Drug Administration that the Myozme drug produced in Allston to treat Pompe disease is equivalent to the drug produced at a much smaller factory in Framingham. It now hopes to win FDA approval for the plant in May.
But because of the difficulty in copying biologic drugs, some advocates contend that any generic versions must be rigorously tested to make sure they are safe and effective - instead of just relying on the data for the original brand-name therapy. But requiring clinical trials would also be likely to deter some generic competitors, because trials typically take years and cost tens of millions of dollars or more. So far, Congress appears to be leaning toward leaving it up to the FDA to decide case by case.
In addition, generic and biotech lobbyists are bitterly divided over how long biotech companies should be able to keep their monopoly on a drug before facing competition from generics.
The generic drug industry has proposed that Washington use the same formula set up for traditional generic drugs, called the Hatch-Waxman Act. Under that 1984 law, drug makers are protected from competition for at least three to five years (plus the life of their patents).
"For the last 25 years Hatch-Waxman has been working tremendously well," said Kathleen Jaeger, president of the Generic Pharmaceutical Association, adding that there's no reason to think it won't work for biologic drugs.
But the biotechnology trade group contends companies deserve 14 years of "market exclusivity," because patent protection may be less meaningful when it comes to biologic drugs.
Executives say it takes longer to develop biotech drugs, eating up a valuable chunk of patent protection before a drug even reaches the market. And even if a patent is still in force, the group argues, generic companies might have an easier time "designing around" the patents - since biogenerics need not be exact copies of the original drugs.
"Patents don't protect us," said Jim Greenwood, president of the Biotechnology Industry Organization. Greenwood said traditional drugs are currently on the market an average of nearly 14 years before they face generic competition, so it only makes sense to give biotech companies the same protection.
Last year, Democratic senators Edward Kennedy of Massachusetts and Hillary Clinton of New York, along with Republicans Orrin Hatch of Utah and Mike Enzi of Wyoming, proposed a compromise that would give drug makers 12 years of protection for each drug, two years less than the biotech industry had proposed.
"Its provisions balanced the important goals of improving access to low-cost drugs while preserving the incentives needed for innovation to thrive," Kennedy said in a videotaped speech scheduled to be presented at the Northeastern conference.
And Representative Anna Eshoo, a California Democrat, recently teamed up with Representative Joe Barton, Republican of Texas, to propose rival legislation. It would give biotech companies 12 to 14.5 years of market protection, something the generic industry opposes as too much.
Last year, Eshoo made it clear she wants to make sure that biotech companies have strong incentives to continue developing life-saving therapies.
"We should look at ways to make biologic products more cost-effective," she said. However, "There will be nothing to copy if we don't ensure sufficient incentives exist to develop these already life-saving medicines in the first place."
Both sides expect some version of a bill to pass this year or next. But it will still probably take at least two more years for regulators to put new rules in place and for generic drug makers to win FDA approval to market the discounted drugs.
Meanwhile Cambridge-based Momenta is working with Novartis
"We look at it as a tremendous opportunity because of the large size of the biologics marketplace," said Momenta's chief executive, Craig Wheeler.
And in a twist, Momenta hopes to use its expertise to do more than copy existing drugs - taking what it learns in the process to make even better versions of the drugs.
Unlike traditional drugs, Wheeler argues, the biology of many new biotech drugs is not well understood, leaving plenty of room for improvement.
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The introduction of new bipartisan legislation on generic biologics, which is expected later this week, is likely to jump-start negotiations over how to approve this subset of drugs, with some industry lobbyists hopeful that the measure could attract a critical mass of support for language favorable to name-brand manufacturers.
The bill < the Pathway for Biosimilars Act, sponsored by Reps. Anna Eshoo(D-Calif.) and Joe Barton (R-Texas) < would propose a pathway for approving generic biologics, which include vaccines and antitoxins made from living organisms.
The legislation hews closely to what brand-name biologics makers, including those represented by the Biotechnology Industry Organization, have sought, according to a draft copy of the bill provided to CongressNow. The BIO approach is to provide companies that invent biologics with 14 years of exclusivity.
The Eshoo-Barton bill would provide 12 years of data exclusivity and an additional two years for approval of a medically significant new indication. The bill would also provide an additional six months of exclusivity for approval of a product for use in pediatric populations.
Another factor at stake is interchangeability < that is, whether a generic version of the biologic can be considered equivalent to the brand product. The Eshoo-Barton bill would require that the Food and Drug Administration issue a guidance advising that it is feasible to make a determination of interchangeability for a product class before generics could be approved.
Both BIO and the Generic Pharmaceutical Association agree on the need for a pathway to approve these products, but they are far apart on the details, particularly regarding the period of exclusivity.
GPhA rejects BIO's position on exclusivity, arguing that the current five-year patent protections are sufficient. The group was also quick to blast the bill as a brand industry "wish list," Kathleen Jaeger, GPhA's president and CEO told CongressNow.
However, regardless of their differences, both groups believe that this bill could help move the debate for a biologics pathway forward.
Jim Greenwood, BIO's president and CEO, told CongressNow that the legislation could provide a platform for brand companies to win the debate over exclusivity. If this bill's supporters are able to get on the same page as supporters of similar legislation (H.R. 1956) offered by Rep. Jay Inslee (D-Wash.), they could have the numbers to move legislation with a greater period of exclusivity out of the House Energy and Commerce Committee's Subcommittee on Health.
The legislation is "jump-starting the talks," Jaeger said. But a GPhA official dismissed the notion that merging the two bills would drive through legislation favoring the brands. The majority of organizations oppose such a long period of exclusivity, making it uncertain whether there would be enough support among lawmakers to move a bill with 14 years of exclusivity out of the committee, let alone the full House.
Broader political realities loom over the debate. Leading Democrats, including House Oversight and Government Reform Chairman Henry Waxman (D-Calif.), may be willing to hold up legislation until the next administration is in office, believing that then a more generic-friendly bill will be likely then, various lobbyists have said. Republicans have generally been friendlier to the drug industry than Democrats have in recent years, with many Democrats historically favoring generics.
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House Energy and Commerce ranking member Joe Barton, R-Texas, is on the verge of introducing legislation with Rep. Anna Eshoo, D-Calif., that would allow FDA to approve generic versions of biologic drugs. House Republicans have been relatively quiet on so-called follow-on biologics, while Democrats have openly backed two bills that fall on opposite ends of the spectrum as far as their appeal to biotechnology companies.
Stakeholders have expected Eshoo to introduce a bipartisan bill at any moment in the last few months, but lately have been wondering if she was going to produce one.
"We still have a few more details to work out, but we're really, really close," Barton said Thursday.
Eshoo hasn't released details of her bill, but Barton said the draft would grant brand biologic companies 12 years of exclusivity before FDA can approve a low-cost follow-on biologic.
The Senate Health, Education, Labor and Pensions Committee passed a bipartisan follow-on biologic bill in the summer that included 12 years of exclusivity. Barton said one of the details he and Eshoo are working out is whether follow-on biologics are interchangeable with brand biologics. If FDA were allowed to deem follow-on biologics interchangeable,pharmacists would be allowed to substitute a follow-on for a brand biologic.
Energy and Commerce Health Subcommittee ranking member Nathan Deal, R-Ga., had planned to work across the aisle with Health Subcommittee Chairman Frank Pallone, D-N.J., and was not pleased with Barton's decision. "I had hoped he wouldn't do that," Deal said when told Barton was going to co-sponsor Eshoo's bill.
Deal said the Barton/Eshoo bill is more protective of the biotechnology industry than he thinks is warranted. Deal and Pallone won't likely have a bill to counter Barton and Eshoo's any time soon, though.
Deal said he has informally talked with Pallone, but they haven't dug into the specifics and aren't sure when they will. "The sides have shifted as to who has the urgency right now," Deal said. The biotechnology industry has pushed hard to pass a bill before the next election, banking on getting a better deal while President Bush is in the White House. The generic industry has appeared to back off in recent months from jockeying for a better deal should a Democrat win the presidency.
"[The election] is a factor, obviously, in terms of who is prodding and who is kind of sitting back," Deal said.
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The effort to give the FDA authority to approve follow-on biologics, which had slow progress in Congress last year, may be picking up momentum as part of a new initiative to improve access to affordable healthcare.
Reps. Allyson Schwartz (D-Pa.), Lois Capps (D-Calif.) and Jason Altmire (D-Pa.), all members of the New Democrat Coalition, are leading the effort, which also includes implementing eprescribing. The lawmakers are involved with the three House committees primarily in charge of healthcare policy Ñ including the Energy and Commerce Committee, where follow-on biologics legislation has been introduced.
House lawmakers are considering multiple bills, including Rep. Henry Waxman's (D-Calif.) Access to Life-Saving Medicine Act, H.R. 1038, which would let the FDA approve biosimilars as interchangeable with the reference biologics, and Rep. Jay Inslee's (D-Wash.) Patient Protection and Innovative Biologic Medicines Act, H.R. 1956, which would not let biosimilars be deemed interchangeable.
A spokeswoman for Energy and Commerce Committee Chairman John Dingell (D-Mich.) said the committee has not yet finalized its agenda for this session but noted that the committee is expected to address the issue of biosimilars in the near future. Similarly, a spokesman for Rep. Frank Pallone (D-N.J.), chairman of the House Health Subcommittee, said Pallone continues to work with committee members to reach a consensus on follow-on biologics legislation.
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On February 4, 2008, FDA announced that the Bush Administration is requesting nearly $2.4 billion ($1.77 billion in budget authority and $628 million in user fees) for the Agency as part of the Fiscal Year 2009 budget. Of particular interest in the proposed FY2009 budget are several proposals related to follow-on biologics, new user fees, and resurrecting the Direct-To-Consumer ("DTC") television ad user fee program created by the FDA Amendments Act ("FDAAA").
Follow-On Biologics
The coming year will likely see a significant push to pass legislation creating follow-on biologics (also referred to as "generic biologics"). According to the budget proposal:
For FY 2009, the Administration will seek new statutory authority to allow FDA to approve abbreviated applications for certain biologic products licensed under the Public Health Service Act (PHS Act). . . . The legislative proposal will include necessary provisions to ensure the safety and effectiveness of these biologic products for patients. The proposal will include a predictable and public guidance process for licensing follow-on protein products under the PHS Act. The proposal will prescribe the type of data required for FDA to review applications for follow-on protein products and will require labeling for the safety concerns related to the interchangeability of these products. In addition, the proposal will include adequate intellectual property protections to preserve continued robust research into new and innovative life-saving medications. The Budget proposes a new authority for FDA to approve follow-on protein products through a new regulatory pathway that protects patient safety, promotes innovation, and includes a financing structure to cover the costs of this activity through user fees.
In 2007, the U.S. Senate Health, Education, Labor, and Pensions Committee voted on legislation approving amendments to the Public Health Service Act to add ¤ 351(k) to provide for an approval pathway for "biosimilar" and "interchangeable" biologics that rely, in part, on FDA's previous licensure of an innovator's product. At the time, it was thought that such legislation might be included in the U.S. Senate's version of FDAAA. Support for the bill fell apart, however, due to differences of opinion over the length of exclusivity for innovator products. (See FDA Law blog post here). In addition, the Bush Administration objected to including follow-on biologic provisions in FDAAA.
We understand that the Biotechnology Industry Organization ("BIO") is vigorously lobbying Congress on draft legislation. Information on BIO's position is available here.
New User Fees
President Bush's FY2008 budget request included a proposal with draft performance goals to create a generic drug user fee program. The FY2009 request includes a similar proposal, but without draft performance goals. The program, which the Administration will formally introduce in draft legislation later this year, includes estimated FY2009 spending of $16.6 million.
The Bush Administration's FY2009 budget proposal also includes new user fee programs for activities that are currently funded through discretionary appropriations, including:
DTC TV Ad User Fee Program
FDA's FY2009 budget proposal states that the Bush Administration plans to resurrect the DTC television ad user fee program added to the Prescription Drug User Fee Act ("PDUFA") by FDAAA. We previously reported that the new user fee program would not launch due to inadequate congressional funding, notwithstanding significant industry interest in the program. As a result, FDA did not send out invoices, and the 120-day trigger in FDAAA for collecting adequate funding from industry participants was not met. Nevertheless, "[t]he budget for FY 2009 contains user fees to support the review of direct to consumer television advertisements, as authorized by PDUFA. The Administration will work with Congress to modify the 120-day requirement in FDAAA to ensure that FDA can operate the DTC-TV program in FY 2009."
http://www.fdalawblog.net/fda_law_blog_hyman_phelps/2008/02/president-bush.html
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The generic drug industry has fought hard for legislation that would allow FDA to approve generic biological medicines as "interchangeable" with the brand-name products they copy. But FDA's chief medical officer said last week that the industry might be exaggerating FDA's ability to make that determination, as well as the value of the term itself.
Speaking at the annual policy conference of the Generic Pharmaceuticals Association, FDA Chief Medical Officer Janet Woodcock said it would be "naive" to think a generic biological medicine could be considered identical to its branded counterpart. She called on the industry to "fess up" to that fact.
"We cannot be convinced that two proteins are exactly the same," Woodcock said.
The debate over biogenerics legislation has been consumed largely by whether follow-on biologics could be classified as "interchangeable" with or "equivalent" to brand products. Although a standard of "sameness" hasn't been officially proposed, generics companies have lobbied hard for a label as close to synonymous as possible.
"Just because you've relied on another product to get your product approved doesn't mean those products can be freely switched back and forth with no consequences," Woodcock said.
She expects that some drugs will be switch-able and some will not, but said FDA doesn't have the science to make those determinations as accurately as it would need to. Although some drugs can demonstrate their similarity to brand-name biologics largely through a scientific description, Woodcock said, those methods don't work with inhaled or otherwise locally acting products. In those cases, she said, FDA's best option for now is to require a head-to-head clinical trial comparing the two products.
Requiring generic makers to conduct the expensive, time-consuming trials would likely undercut their basic business model -- cheap drugs, approved quickly because they simply copy another approved product.
Woodcock said better data collection tools, including FDA's Critical Path Initiative, will be instrumental to an expedited approval path. Taking care not to comment on pending legislation, Woodcock said she was less concerned with the existence of a pathway than its scientific validity.
Reviewers in FDA's Office of Generic Drugs have seen their workload increase dramatically in the past several years, but the number of new employees has not kept up. Woodcock said that as FDA moves toward a more technically advanced approval path, it will also be able to expedite approvals by relying more heavily on manufacturers' data.
"Frankly, what we do in-house, as the government, our oversight methods are costly for us, and they're slow," she said.
She did not address the merits of a user fee for generics, akin to the one brand-name companies pay in exchange for expedited review. Outgoing FDA Chief Counsel Sheldon Bradshaw endorsed a generics user fee in his remarks at the same conference. He cited some of the same staffing shortages Woodcock mentioned, and said the problem was too large to be fixed through congressional appropriations.
During a question-and-answer session, one conference attendee said Woodcock's hold-your-horses approach to an abbreviated approval pathway for biogenerics sounded suspiciously like the position of the Biotechnology Industry Organization.
"All the legislation in the world isn't going to give us scientific capacity we don't have," Woodcock responded. "I don't know that the basic scientific facts are that much in dispute."
The question of whether FDA has that scientific capacity, however, appeared to be very much in dispute. Woodcock's measured analysis was followed immediately by a speech from Christopher Begley, the chairman of Hospira, Inc., in which he said FDA is prepared to meet what he framed as a moral obligation.
"The science is ready, the industry is ready, the FDA is ready," he said. "The facts all line up. There is no gray, but we wait."
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Prescription medications are among the most thoroughly regulated and scrutinized products on the consumer market. Years of development of a single drug are followed by several more of rigorous testing under stringent federal oversight.
There is good reason for this. The result is peace of mind for the consumer that each drug is not only safe and effective, but that every individual pill within a prescription bottle is identical to all the others.
The quality and safety of an emerging field of biotech drugs, or biologics, could be put at risk under legislation that some members of Congress are attempting to push into law too expeditiously.
The bill, sponsored by Rep. Henry Waxman, D-Calif., would lower the universal standards for biologics and fail to provide promising upstart companies with reasonable exclusivity rights to their data.
Biologics are the fastest growing sector of the drug market, resulting in breakthrough treatments for heart disease, Alzheimer's, multiple sclerosis and others. But without careful review and the proper requirements for clinical testing, patient safety is sacrificed.
When creating a generic drug of a traditional pharmaceutical, drug manufacturers need only to copy a scientific formula and create the same result multiple times. Reproducing biologics is much more complex because they are developed from complicated and diverse living organisms. They are difficult to produce safely and the slightest change in the process could result in a useless or even harmful drug.
The legislation moving through Congress fails to acknowledge that manufacturing biopharmaceuticals is much more complex than making chemical drugs and requires greater scrutiny and testing. Legislators must take the necessary time to understand that biologics are unique and that, unlike the chemical pharmaceutical industry, current scientific and marketing capabilities are not sufficient to produce biologic generics that are exact replicas of the original product.
Congress made patient safety a top priority when insisting two decades ago that generic copies of chemical pharmaceuticals must be identical to their brand-name counterparts. As a result, generic companies matched the formulas and processes approved by the FDA and consumers had the peace of mind that their drug was no different from the brand-name they trusted.
This simply isn't possible yet with biologics. If generics can't be made identical to the drugs they copy, they should at minimum be tested to make sure they're as close as possible. Anything less threatens patient safety.
The generic drug bill passed 20 years ago was good for American health care consumers, saving an estimated $8 billion to $10 billion a year. But that success doesn't guarantee that expanding the program to biologics would be in the best interests of patients without serious study and scrutiny.
While we must work toward ensuring effective medications are made affordable to the general public, a rush to produce cheaper drugs at the expense of patient safety is shortsighted. Congress should seek to control long-term costs while ensuring patient safety.
State Rep. Peter Koutoujian, D-Waltham, is the House Chairman of the Joint Committee on Public Health.
http://www.metrowestdailynews.com/columnists/x875178377
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Pharmaceuticals
VACAVILLE, Calif.
THE cancer drugs produced at Genentech's gleaming factory here are the vanguard of 21-century biotechnology. But the way the drugs are made is borrowed a bit from a more ancient industry of Napa Valley.
Wine and biotech drugs are both made by growing cells, usually in stainless-steel tanks. But rather than using yeast to convert sugar to alcohol, biotechs use genetically engineered animal or bacterial cells to make proteins from nutrients.
The process for both is part art, part science. Results can differ from factory to factory, or even between lots in a single site. While wine lovers savor the differences among vintages, patients could be hurt by inconsistencies in drugs.
Such vagaries lie at the heart of a debate going on in Congress Ñ whether pharmaceutical companies can be allowed to make generic, low-priced copies of the drugs originated by Genentech and other biotech companies. Genentech says the pharmaceutical companies should not be allowed, arguing that other companies could not replicate its drugs precisely because the process is so complex.
Genentech says the Vacaville plant is one of the largest factories in the world making genetically engineered drugs using animal cells. The plant was built in the 1990s for more than $400 million and has tanks with a capacity of 144,000 liters (about 38,000 gallons) to produce the drugs Avastin, Rituxan and Herceptin for cancer and Xolair for asthma.
These drugs, which are proteins, are made by splicing a human or other gene that has the recipe for the protein into another cell, creating a master bank for each drug.
For simpler biotech drugs like insulin and growth hormone, bacterial cells are usually used. But for the more complex proteins made here, bacteria are not up to the task. So Genentech uses cells from Chinese hamster ovaries, which have become an industry standard.
At Vacaville, scientists take a small vial of cells from the master bank and multiply them until they fill a steel vessel that is nearly two stories high and produces mass quantities of the drug. If all goes well, the process takes about three weeks.
But everything doesn't always go well because the cells normally grow inside hamster ovaries. "Any cell line, at any point in time, can go, 'I'm tired,' " and stop growing, said Mark Fischer, a production specialist for Genentech. "You may not know why."
When the factory first opened, the cells for making Herceptin would not grow. Company scientists found that traces of tungsten were leaking into the vats from bearing seals, poisoning the broth.
One cannot simply pour a few cells into a huge vat and wait for them to multiply. Rather, the finicky cells must acclimatize to larger and larger tanks. At this factory, the contents of the original vial are poured into a three-liter flask. When the cells fill that, they are transferred to a 20-liter steel tank. When that is filled, they are moved into vessels of 80 liters, 400 liters, 2,000 liters and finally 12,000 liters, or about 3,200 gallons.
At each step, the cells are fed a secret sauce of sugars, amino acids, proteins and hormones like insulin. Inside the vessels, paddles stir the mix.
All the manufacturing is done under strict sanitary conditions. Workers wear jumpsuits, gloves, booties and covers for their hair and beards. The cells and other ingredients are not exposed to the environment, but are pumped into the sealed vessels through hundreds of miles of pipes.
When the 12,000-liter tank is full, the drug is separated from the cells, the other proteins made by the cells and the nutrient mix. This process isolates the desired protein based on its density, electric charge, molecular weight and chemical affinity. Once the protein is 99.9 percent pure, it is frozen and shipped to other plants for packaging.
Subtle changes in conditions can change the drug. When Genentech transferred production of its psoriasis drug, Raptiva, from a 2,000-liter tank at a partner's factory to its own 12,000-liter tank, tests showed that the drugs had changed, even though the same cell lines were used.
The Food and Drug Administration required that Genentech conduct new clinical trials to show that the drug worked as well as the drug that had been made by the partner. That process delayed approval of Raptiva by nearly two years.
Congress is considering legislation that will allow pharmaceutical companies to make "biogenerics," or "biosimilars," for much lower prices than the original biotech drugs, which can cost patients and insurers tens or even hundreds of thousands of dollars a year.
Genentech executives argue that generic drug companies could never precisely replicate biologics, as these drugs are called, as they can simpler pills made from chemicals.
"The minute you change the cell line, you're going to make a different product," said Robert L. Garnick, senior vice president for regulatory affairs, quality and compliance at Genentech.
And as the case with Raptiva shows, the product can come out differently even using the same cell.
Company executives say that makers of biogenerics should be required to conduct clinical trials on humans to prove their drugs are safe and effective. That requirement would increase the time and cost of taking the drugs to market.
Companies that want to make biogenerics say that analytical techniques are becoming sophisticated enough to ensure that their drugs would be as safe and effective as the originals.
Theresa L. Gerrard, a consultant to the Generic Pharmaceutical Association, said that biotechnology companies often tweak their processes but do clinical trials only if analytical tests show the drugs differ, she said.
Moreover, she added, perfect replication is unnecessary because the drugs that Genentech produces also vary slightly from lot to lot.
"We're not asking for a lower standard," Dr. Gerrard said. "We're asking to use the standard that has been in place at the F.D.A. for 15 years."
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AS AMERICAN families face the rapidly escalating costs of staying healthy, health care industry experts and politicians each year have brought proposals to the forefront to take pressure off increasing costs. One key milestone for controlling costs was an action taken by Congress in 1984 dramatically changing the generic drug approval process. This legislation, the Hatch-Waxman bill, expanded the number of options for consumers by creating a process to move more generic drugs into America's pharmacies, saving consumers an estimated $8 billion to $10 billion a year.
There is little debate that generic drugs benefit the consumer when the process for approval is strict, closely monitored, and regulated with patient safety in mind. Generic drugs are as safe as brand-name drugs because the 1984 legislation empowered the Federal Drug Administration to ensure that generics use the same active ingredients and are shown to work the same way, producing the same benefits -- and risks -- as their brand-name counterparts. When approving generics, the FDA requires them to have the same quality, strength, purity, and stability as their brand-name counterparts to ensure that they work in exactly the same way.
Unfortunately, there are now efforts in Congress to lower those standards in regard to the emerging field of biotech drugs, or biologics. Produced from living cell cultures rather than synthesized chemically, biologics are the fastest growing component of the drug market, treating cancer, Alzheimer's, heart disease, diabetes, multiple sclerosis, AIDS, and arthritis, among many others.
Massachusetts has a distinct edge in the biotechnology field, with dozens of companies developing products today to treat and possibly cure debilitating and deadly diseases. But without the proper protections in place to ensure that these products meet the highest clinical standards and protect the intellectual property of innovator companies, we could be threatening the future of this dynamic field.
The rush by some in Congress to create a new market for generic drug makers in the field of biologics would actually sacrifice patient safety over the long term. The challenge Congress and regulators face as they seek to create a path for follow-on biologics is that the process of making biopharmaceuticals is much more complex than making chemical drugs and requires greater scrutiny and testing. Effective generic biologics would be extremely difficult to produce safely because these products are developed from complicated and diverse living organisms. The slightest change in process could render the drug useless or even dangerous. Traditional chemical pharmaceuticals simply require generic drug manufacturers to copy a scientific formula to produce the exact same result time after time.
This legislative effort may also be putting in jeopardy the very economic situation that has enabled the biotechnology field to surge in Massachusetts by lowering standards for patient safety and failing to provide proper intellectual property protection.
Companies in the early stages of developing a product rely on financial support to complete the research and development process. By jeopardizing that support, the discovery of innovative medicines could be stifled.
As Congress presses forward, legislators and regulators must take the time to understand that biologics are very different from traditional chemical pharmaceuticals and that, unlike the process for producing generic versions of chemical drugs, current scientific capabilities are not sufficient to produce generic biologics that are exact replicas of the original products.
The introduction of follow-on biologics may indeed eventually provide patients a more affordable alternative to life-saving medicines, which is a laudable goal. But given the highly complex processes involved in creating and manufacturing biologics, Congress and the FDA must be deliberative and careful before allowing generic companies to do their best to replicate proven biologic treatments. Let's move toward more affordable solutions, but do so with an approach that helps to ensure both the safety of patients and the incentives needed to help keep Massachusetts biotechnology companies in the business of creating new cures.
Una S. Ryan is president and chief executive officer of AVANT Immunotherapeutics Inc.
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The leadership of The New Democrat Coalition, 60 moderate Democratic members of the House of Representatives, on May 23rd announced they were supporting Rep. Jay Inslee's approach to creating a pathway for FDA approval for "follow-on biologics" rather than the bill sponsored by Rep. Henry Waxman.
The bill introduced by Inslee (D-WA), a member of The New Democrat Coalition, is more protective of innovator biologic drugs than Waxman's bill, and would make it more difficult for generic manufacturers to demonstrate that a similar biologic product is safe and effective.
"America's patients want new cures, and they deserve access to lower-cost biological medicines. That's why the FDA needs the authority to approve follow-on biologics. Congressman Inslee's legislation will do just that while ensuring patient safety and the continued medical innovation for which America is world-renown," said coalition Chair Rep. Ellen Tauscher (D-CA).
"This bill would ensure we can move toward greater access to this care while providing clear safety guidelines and adequate protections for the innovators," said coalition Vice-Chair Rep. Ron Kind (D-WI).
"The Inslee legislation is a commonsense proposal that will increase Americans' access to affordable, life-saving therapies," added coalition Vice-Chair Rep. Joe Crowley (D-NY).
"Unlike other proposals, this bill helps ensure the United States remains an attractive place for innovators to develop new pharmaceutical treatments," said coalition Vice Chair Rep. Adam Smith (D-WA).
"We should encourage competition in biologics, but the approval pathway must
include rigorous standards in order to protect consumers and reward
innovation. I see H.R. 1956 as a good starting point for negotiations," said
said coalition Vice-Chair Rep. Artur Davis (D-AL).
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Congress is rumbling to life on pharmaceutical prices, and the cause du jour is biotechnology medicine. Both chambers are considering legislation that would allow for the manufacture of lower-cost "generic" copies of biopharmaceuticals. Proponents of the plan speak a language of easy certainties, but the issues -- and potential consequences -- are vastly more complex.
Biopharmaceuticals, or biologics, are proteins made by splicing genetic material into living cell cultures. Many biologics are breakthrough therapies, from Avastin, which chokes off the blood supply to cancerous tumors, to Cerezyme, which treats the rare genetic disorder Gaucher's disease. These drugs are expensive: Some can run to thousands of dollars a year. According to IMS Health, the total cost reached $52.7 billion in 2005, some 13% of U.S. drug spending. That figure is expected to rise to $90 billion by 2009.
California Representative Henry Waxman has introduced the Access to Life-Saving Medicine Act because, he claims, all this is "too expensive." The reference point is the law Mr. Waxman co-authored in 1984 allowing the Food and Drug Administration to approve cheaper, generic versions of conventional drugs once the patents on the originals expire. When the Hatch-Waxman act went into effect, however, biologics were barely on the medical horizon. The new bill -- also sponsored by Senators Hillary Clinton and Chuck Schumer -- would establish a similar regulatory chute for approving "biogenerics."
But this is an attempt to fit a new problem into a framework for which it wasn't designed. The pharmaceuticals currently covered under Hatch-Waxman are "small-molecule" drugs made through distinct and replicable chemical syntheses. Simple tests can show that a generic is chemically identical to the original. The same can't be said for biologics: Because they are made from living cells, a generic will not be biochemically identical to the original. For this reason, "biogenerics" are called "follow-on biologics" by the FDA. The FDA's European counterpart calls them "biosimilars."
The long protein chains in biologics are less well understood than traditional drug molecules. Protein folding, glycosation or impurities introduce variation, sometimes with adverse side-effects. In the late 1990s, Johnson & Johnson sold a licensed version of Amgen's dialysis drug Epogen, called Eprex in Europe. Several hundred patients developed a serious immune reaction called pure red call aplasia due to a minor change in the manufacturing process.
Follow-on versions of some of the most basic biologics, like human insulin and human growth hormone, are either on market or undergoing FDA review. As the science becomes more sophisticated, the same will be possible for more complex biologics. Right now, it isn't.
Nevertheless, the Waxman legislation would establish "interchangeability," or therapeutic equivalence, as the FDA standard: A prescription for expensive Avastin, say, could be filled by a cheaper generic product, even though the two might function differently in the body. The legislation also enforces an abbreviated FDA review process, circumventing the multiyear clinical trials and postmarket studies required of the original drugs. It even restricts the FDA's authority to require postmarket tests, in effect assuming into the process facts not in evidence.
While some of the concerns about the potential side-effects of biosimilars may be overstated, doctors and patients ought to have access to the clinical data that would allow them to evaluate for themselves the risk-reward trade-offs. In that regard, it would be useful to ease the FDA's onerous safety and efficacy regulations. But Mr. Waxman's proposal to do so selectively, only in the case of biosimilars, suggests other motives.
The animus at work here seems to be to tilt advantages away from Bio Pharma toward the generics. Mr. Waxman's bill would weaken intellectual property protections such as clinical trial data exclusivity, and also establish compulsory licensing. Further, it offers incentives for generics to work around the many patents that cover complex biologics before they expire. Even the EU provides more stringent patent guarantees for biosimilars.
The high prices of biologics reflect the difficulty and expertise required to develop these
medicines. It should be possible to preserve incentives to innovate while advancing
legitimate public health goals like increased access. And generics can play a useful role
in spurring the reformulation of existing medicines in more efficacious ways. The
challenge is to strike a balance between access and innovation, which Mr. Waxman and
his allies fail to do. The real costs of this agenda might well be fewer new biological
therapies.
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WASHINGTON (AP)--A top drug regulator told lawmakers Monday it could be a decade or more before science is available to approve generic versions of biotech drugs in the way the agency approves knockoffs of traditional drugs.
Food and Drug Administration deputy commissioner Janet Woodcock's testimony could benefit companies such as Amgen Inc. (AMGN) and Genentech Inc. (DNA), which have never faced generic competition in the U.S. for their products, some of the most complex and expensive on the market.
That lack of competition would change under a bill recently introduced by Rep. Henry Waxman, D-Calif. The bill would task FDA with approving knockoff versions of biotech medicines, many of which cost tens of thousands of dollars for a year's supply.
Waxman, who chairs the House Committee on Oversight, helped launch the generic drug industry more than 20 years ago when he co-wrote legislation allowing generic manufacturers such as Barr Pharmaceutical Inc. (BRL) and Mylan Laboratories Inc. (MYL) to market cheaper versions of traditional drugs after the originals lose patent protection. Waxman's new legislation would give generic drug makers access to an estimated $12 billion worth of biotech patents that have already expired.
Unlike traditional chemical-based pharmaceuticals, biotech pharmaceuticals are made from living cells and proteins. The biotech industry has long argued that because these proteins are more prone to minor differences when mass produced, it will be more difficult for generic drug companies to reproduce them safely.
Woodcock said that while FDA can currently establish the safety between versions of simple protein-based drugs, it will likely "be a stepwise progression over a decade or so," before the agency can scientifically verify that a knockoff version of a complex biotech drug is similar to the original. Woodcock testified before the House oversight committee along with representatives from the drug industry and consumer groups.
Ranking member Tom Davis, R-Virginia, argued that the complexity of biotech drugs makes it essential that would-be generic biotech makers be required to conduct clinical trials of their products.
A vice president from Denmark-based Novo Nordisk (NVO), a biotech company that makes diabetes therapies, agreed. Nordisk's Inger Mollerup said that if Congress creates a system to approve cheaper protein-based drugs it should be similar to one already used by the European Union.
Under the EU system, generic biotech companies have to conduct extensive studies to show the safety of their versions. Even after these studies are completed and the product is approved, knockoff biotech drugs are not considered interchangeable with the original product, meaning a patient has to get doctor approval before switching from the original drug to a generic.
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WASHINGTON (Reuters) - Cheaper, generic versions of more complex protein-based drugs will need more data than simpler compounds to prove their safety and effectiveness, a U.S. Food and Drug Administration official said on Monday.
"The amount of assurance and the amount of data that would be needed is really based on how complex something is and how well it can be characterized," FDA Deputy Commissioner for Operations and Chief Medical Officer Dr. Janet Woodcock told lawmakers.
Other factors, including whether a drug would be used long-term for chronic diseases, will also impact what kind of testing will be needed, she added during a hearing of the U.S. House of Representatives Committee on Oversight and Government Reform.
Her comments come as Congress weighs legislation to give the FDA authority to approve generic versions of biological medicines such as Genentech Inc.'s cancer drugs Herceptin and Avastin, as well as anemia drugs such as Amgen Inc.'s Epogen and Aranesp and Johnson & Johnson's Procrit.
Unlike conventional, chemical-based drugs, biologics are derived from living cells and are usually injected or infused.
At issue is whether generics could be considered either interchangeable or similar to their more expensive counterparts, and how Congress should set standards.
The FDA already has the power to clear generic versions of traditional medicines. More than 9,000 such products are already on the U.S. market and make up 60 percent of all prescriptions, according to the agency.
Committee Chairman Henry Waxman, the California Democrat who convened the panel, has introduced legislation that would allow the FDA to review generic biologics. A similar bill has been introduced in the Senate.
Brand name drugmakers and other opponents say biologics are too difficult to duplicate and even small differences can affect safety and efficacy. But supporters, including insurers and patient groups, argue competition would make them more affordable than branded versions that can cost tens of thousands of dollars a year.
At the hearing, Woodcock said the FDA has the expertise to evaluate such generics, also known as follow-on biologics, but the ability to compare them to original products will depend on the molecule's complexity.
Some biologics, such as insulin or human growth hormone, are considered simpler than other proteins used to treat cancer, anemia and other conditions.
"Although this may be currently possible for some relatively simple protein products, technology is not yet sufficiently advanced to allow this type of comparison for complex protein products," she said in her testimony.
When asked how long it would take technology to catch up, Woodcock said it would be an ongoing process.
"It's going to be a step-wise progression over a decade or so," she said.
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A top drug regulator told lawmakers Monday it could be a decade or more before science is available to safely approve generic versions of biotech drugs in the way the agency approves knockoffs of traditional drugs.
Food and Drug Administration deputy commissioner Janet Woodcock's testimony could benefit companies such as Amgen Inc. and Genentech Inc., which have never faced generic competition in the U.S. for their products, some of the most complex and expensive on the market.
That lack of competition would change under a bill recently introduced by Rep. Henry Waxman, D-Calif. The bill would task FDA with approving knockoff versions of biotech medicines, many of which cost tens of thousands of dollars for a year's supply.
Waxman, who chairs the House Committee on Oversight, helped launch the generic drug industry more than 20 years ago when he co-wrote legislation allowing generic manufacturers such as Barr Pharmaceutical Inc. and Mylan Laboratories Inc. to market cheaper versions of traditional drugs after the originals loose patent protection. Waxman's new legislation would give generic drug makers access to an estimated $12 billion worth of biotech patents that have already expired.
Unlike traditional chemical-based pharmaceuticals, biotech pharmaceuticals are made from living cells and proteins. The biotech industry has long argued that because these proteins are more prone to minor differences when mass produced, it will be more difficult for generic drug companies to safely reproduce them.
Woodcock said that while FDA can currently establish the safety between versions of simple protein-based drugs, it will likely "be a stepwise progression over a decade or so," before the agency can scientifically verify that a knockoff version of a complex biotech drug is similar to the original. Woodcock testified before The House oversight committee along with representatives from the drug industry and consumer groups.
Ranking member Tom Davis, R-Virginia, argued that the complexity of biotech drugs makes it essential that would-be generic biotech makers be required to conduct clinical trials of their products.
A vice president from Denmark-based Novo Nordisk, a biotech company that makes diabetes therapies, agreed. Nordisk's Inger Mollerup said that if Congress creates a system to approve cheaper protein-based drugs it should be similar to one already used by the European Union.
Under the EU system, generic biotech companies have to conduct extensive studies to show the safety of their versions. Even after these studies are completed and the product is approved, knockoff biotech drugs are not considered interchangeable with the original product, meaning a patient has to get doctor approval before switching from the original drug to a generic.
Waxman's bill would allow the FDA to require clinical safety studies, though it wouldn't make it mandatory.
The question of whether generic drug companies would have to conduct safety trials is critical in determining how much lower generic biotech drugs would be priced than their brand name counterparts. Currently, generic drug companies are able to sell their existing treatments at 20 to 60 percent below the original's price because they are not required to spend time and money conducting safety studies.
Last month, pharmacy benefit manager Express Scripts Inc. issued a report saying generic biotech drugs could save patients and insurance providers $71 billion over 10 years.
The Biotechnology Industry Organization called the study flawed, saying it is impossible to forecast savings from generic biotech drugs without knowing how much testing regulators will require. Even as the industry lobbying group tries to head off Waxman's legislation, several original biotech manufacturers say they support the proposal.
Momenta Pharmaceutical's Vice President Ganesh Venkataraman said his company hopes to develop ways to manufacture protein-based drugs that are interchangeable with the original manufacturer's. To date Momenta's research has focused on developing medicines from complex sugar chains, which are different from proteins.
Insmed Inc.'s Geoffrey Allan went one step further, telling committee members that the generic biotech business "is a business in which we would like to specialize."
"The science has reached a level of sophistication to make this endeavor entirely possible," Allan said. "All we need now is the regulatory go ahead."
Insmed's lead product is a first-of-a-kind biological for children who lack certain growth hormones.
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WASHINGTON (AP) -- Copycat versions of pricey biotech drugs may be relegated to a status below that of generic versions of traditional chemical drugs, the head of the Food and Drug Administration suggested Thursday.
Dr. Andrew von Eschenbach told pharmaceutical executives that such knockoffs would be considered only "similar" to brand-name drugs. The FDA commissioner later told The Associated Press that would mean knockoffs would not be interchangeable, or able to be substituted.
That definition mirrors one used by the European Medicines Agency, the FDA's European counterpart. It would draw a distinction between biotech knockoffs, which the FDA says it still lacks the legal and scientific frameworks to approve, and the generic versions of traditional drugs already available.
Today, traditional drug knockoffs or generics are identical to their brand-name versions and can be swapped or substituted for one another. That would not be the case with a knockoff biotech drug deemed only "similar," even though its effect on patients would be the same.
"We recognize that the end point would be what could be best described as similarity. Similarity in the sense that when a doctor gives you the product - delivered it to a patient - it will achieve an effect that is similar to the effect that we expected from the innovative ... compound," von Eschenbach told the annual meeting of the Pharmaceutical Research and Manufacturers of America, the drug industry group.
Unlike traditional chemical-based drugs, biotech drugs - also called biologics or biopharmaceuticals - are made from proteins taken from living cells. Generally, biotech drugs are far more costly and complex than traditional drugs to both make and copy.
Because of that complexity, the FDA and the brand-name drug industry both maintain it would be difficult to ensure the safety and effectiveness of the knockoffs, sometimes called follow-on protein products.
A bipartisan group of lawmakers recently renewed the push to give the agency that legal authority. The FDA says it continues to develop the scientific guidelines required to consider applications from would-be manufactures of the copycat biotech drugs.
The Generic Pharmaceutical Association says the FDA already has the scientific knowledge to approve knockoffs, just as it now can sign off on the changes made by brand-name biotech companies in how they produce their drugs.
"The commissioner is acknowledging that when brands make changes to their products, they are no longer identical to the approved product, but FDA follows sound science to review and approve these changes. This same sound science will be used to review biogenerics for safety and efficacy," said Kathleen Jaeger, the generic drug industry group's president and chief executive officer.
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There was encouraging news coming from testimony about legislation proposed for regulating generic biologics before the Senate Health, Education, Labor, and Pensions committee on Thursday.
The committee is beginning to understand the importance of having rigorous clinical trials for any generic biologic. Manufacturing a biologic isn't like stamping out a new batch of pills. It is immensely complicated work where inexperienced companies should have to go through stringent clinical trials.
This is good news for patients and their safety and for the biotech companies that have spent millions on developing new biologics.
It is also good news for the pharmaceutical outsourcing industry and contract research organizations such as Parexel, PPD, PRA, ICON, Covance, PharmaNet, Quintiles and others. They will benefit from the projected increase in clinical trials and from their push in the last few years to work with biotech companies. In the short term it could be welcome news for biotech giant Amgen, whose anemia drug Epogen goes off patent in six years...
Sen. Edward Kennedy of Massachusetts is headed on the right track when he suggests that U.S. regulators should follow Europe's lead and require rigorous clinical trials for generic biologics. These trials could be as lengthy and expensive as ones for new drugs in development.
Of course, business owners and the federal government should be concerned about the rising spending on relatively expensive biotech products. As more of these new products go through clinical trials, spending is rising disproportionately.
A middle ground will have to be struck so biopharma companies remain profitable enough to spend the huge amounts of money developing new treatments.
You can read Sen. Kennedy's official statement at the hearing here.
Steve Zisson is managing editor at Thomson CenterWatch.
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WASHINGTON - After percolating for months, the biogeneric debate spilled out on Capitol Hill Thursday at a hearing of the Senate Health, Education, Labor and Pensions Committee, and its overall tone seemed to favor pioneer drugmakers.
Chairman Edward Kennedy (D-Mass.) said the hearing would "help to provide the information the committee needs" to determine if a proposal to allow follow-on biologics should be included in a coming bill on drug safety and the Prescription Drug User Fee Act, though he offered no specifics for precise timing on legislative action. However, he indicated that a bill on follow-ons should be "led by the science," and added that "protecting patient safety is essential" and "innovation must be valued."
Sens. Charles Schumer (D-N.Y.) and Hillary Rodham Clinton (D-N.Y.), along with Rep. Henry Waxman (D-Calif.), have introduced legislation that would give the FDA discretion to determine whether there are clinically meaningful differences between follow-ons and original biologicals, as well as prudence on mandating clinical studies on a case-by-case basis.
The measure aims to provide the agency with "power and flexibility to make science-based decisions," Clinton told reporters after the hearing.
But critics say that the bill, as currently written, sacrifices safety standards for speed and savings, and also poorly accounts for pioneer drugmakers' intellectual property. So in addition to questions on timing, it's also not yet clear how strictly a final bill would adhere to the "Access to Life Saving Medicine Act of 2007," or H.R. 1038. In fact, speculation has arisen that competing legislation could be brought forward that addresses concerns about protecting patient safety and patent rights.
Aside from such gazing into the crystal ball, though, opponents of the bill were generally content with the hearing's outcome.
"We were pleased that folks recognized that these are not interchangeable generics," said Amit Sachdev, the executive vice president of the Biotechnology Industry Organization's health section, "and that science matters."
In addition, he applauded the committee's willingness to examine the debate beyond potential cost savings and also consider complexities around scientific, regulatory and patent questions. Given that range of unresolved issues, Sachdev cautioned against hastily advancing the bill in lockstep with pending user fee legislation. Importantly, he said he walked away with "a clear sense that there's bipartisan support for looking at something other than" the Schumer-Clinton-Waxman proposal. "It seems like [final legislative language] is not going to be around the current draft of the bill that was introduced," he told BioWorld Today, "and that's positive."
Innovator companies and their allies have long angled for a slow, conservative approach for allowing follow-on biologics on the market through a pathway that mandates some degree of clinical trials and other testing for all applications. BIO consistently has called for clinical studies of all follow-ons, a point echoed by the committee's ranking member, Mike Enzi (R-Wyo.), who likened the difference between biopharmaceuticals and chemically synthesized drugs to that between skyscrapers and three-bedroom houses. "One girder out of place could cause the entire structure to fall," he said.
That's the point made by pioneer drugmakers: Changes in manufacturing, no matter how minor, impact the final product's immunogenicity profile and other characteristics. Therefore, there will "always be a need" for clinical studies of follow-ons, testified Johnson & Johnson's Jay Siegel. "To ensure safety and efficacy, testing in humans will be needed."
European regulators have adopted guidelines that require clinical testing for all follow-ons, sometimes to a large degree, depending on the complexity of the original biopharmaceutical. In addition, the Europeans have labeled such products biosimilars, an acknowledgement that they are not exact copies.
The "primary objective" of that framework is "to apply equal standards," as opposed to establishing interchangeability and substitutability, testified Nicolas Rossignol, the administrator of the European Commission's pharmaceuticals unit, via satellite from Brussels, Belgium. "There is no one-size-fits-all approach."
In addition, that system provides a period of market exclusivity for pioneer products, prohibiting follow-on applications until after an 11-year period of data exclusivity expires, which innovator companies say is essential. The Schumer-Clinton-Waxman proposal makes no such provision.
Sen. Orrin Hatch (R-Utah), who has predicted that some form of follow-on legislation would pass this year, backed the European method. He said that system should be given "every consideration" in crafting a final bill, adding that he doesn't "quite agree" with existing language in the proposed bill.
In contrast, generic drugmakers favor the flexibility the legislation would give the FDA in determining when an abbreviated application process for follow-ons is applicable, relying on pioneer products' safety and efficacy data for reference in such cases. They believe the measure does not shortchange purity and potency, claiming that manufacturing discrepancies are inherent in the production of all biopharmaceuticals.
"Product is not the process," testified Sandoz GmbH's Ajaz Hussain. "Batch to batch variation is inevitable for all biologic drugs."
The Generic Pharmaceutical Association (GPhA) said that because pharmacokinetic studies are used in conjunction with advanced analytical tools to detect major brand product differences in post-approval manufacturing and product changes, relying on clinical studies to determine treatment outcomes would prove more cumbersome and less precise. Avoiding clinical work would save time and capital, allowing biogeneric makers to price their products measurably below original biopharmaceuticals, according to some estimates. That's music to the ears of some insurers, pharmacy benefit managers, consumer groups and large employers that have recently thrown their weight behind the bill.
Representatives of those groups, along with generic industry executives, have been in Washington all week to discuss the issue with congressional members. To counter that advocacy, BIO bought advertising in political publications read by lawmakers and their staff members. The ad, written to highlight the "twists and turns" of follow-ons, calls "thoughtful" deliberation "the best prescription for this complex issue."
Catalysts appear in motion for something to take shape. In addition to Hatch's prediction, made at a recent GPhA meeting, Mark McClellan, the former head of the FDA and Centers for Medicare & Medicaid Services, told the same audience that follow-on legislation could indeed pass this year. Whether or not it happens in the same time frame as renewing user fees in the next few months remains to be seen, not to mention an apparent lack of movement in the House of Representatives.
After the hearing, members of Kennedy's staff declined to comment on how quickly the issue would move forward. Clinton also demurred, though she conceded that "this is the beginning of the process."
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WASHINGTON -- Local biotech powerhouses were comforted by yesterday's congressional testimony that urged federal regulators to take a cautious approach to approving generic versions of biologics, including mandatory human clinical trials.
The testimony came during a Senate Health, Education, Labor, and Pensions committee hearing considering a bill that would permit the Food and Drug Administration to approve generic versions of biologics -- drugs based on living organisms and cells.
Senator Orrin G. Hatch, a critic of the proposal, says it lowers safety standards and could jeopardize patients' safety. Hatch, a Republican of Utah, cosponsored legislation that speeds to market generic versions of conventional drugs that save Americans at least $10 billion per year, but he favors requiring generic-biologic manufacturers to test their drugs in humans before approval. Hatch also supports establishing patient registries to track side effects that may not occur until years after patients use a product.
Senator Hillary Rodham Clinton, Democrat of New York and one of the bill's sponsors, said the proposal empowers the FDA "to require whatever is necessary, including clinical trials."
Tim Hunt, a Biogen Idec Inc. spokesman, called the proposal "highly flawed," but said yesterday's testimony included "several positive" developments, including a focus on patient safety and a desire to use clinical trials to "truly understand" the safety and efficacy of generic biologics.
The "hearing has highlighted the very complex medical and scientific issues involved with this legislation, the importance of protecting patient safety, and the importance of the need for greater innovation through biotechnology," Hunt said. The Cambridge company manufactures brand-name biologics, including treatments for multiple sclerosis.
Senator Edward M. Kennedy, who chairs the committee, called biologic drugs "miracle medicines," but acknowledged that some come at a steep price: tens to hundreds of thousands of dollars per year, per patient . Americans spent an estimated $60 billion on such products last year, according to IMS Health, a healthcare information company, compared with $53 billion in 2005 .
Kennedy, Democrat of Massachusetts, said legislation regulating how generics come to market should be "led by the science " while protecting patient safety and valuing the investments made by innovative companies. He favors the approach taken by European regulators, who have approved generic versions of certain biologics, but only after manufacturers conducted rigorous human clinical trials.
Drug manufacturers who testified yesterday were split on whether to mandate clinical trials, which can cost millions of dollars and take years to complete.
"Absolutely, they need to be required," said Dr. Jay P. Siegel, a biotechnology research and development head at Johnson & Johnson . Experimental drugs with the potential of triggering troubling immune-system responses cannot be spotted without such trials, he said. "You could not take a drug that had never been studied in humans under carefully controlled conditions and start selling it to thousands of people," Siegel said. "It just would present too high a risk."
Ajaz S. Hussain, a vice president at Sandoz, the generic-manufacturing arm of Swiss drug maker Novartis AG, said the legislation "should give the discretion to FDA to ask for appropriate data sets that they think are necessary. Clinical [trials] could be part of it, or may not be part of it."
Hussain said demonstrating that a generic is comparable to the original biologic would always require clinical trials. Sandoz collaborates with Momenta Pharmaceuticals Inc. of Cambridge, using the firm's technology to more fully characterize proteins, reducing the number of human clinical trials required.
A broad coalition of businesses and groups supports giving the FDA legal authority to approve generic biologics, in part, because of its potential to shave billions from skyrocketing healthcare spending.
Sid Banwart, a vice president at Caterpillar Inc., the world's largest manufacturer of construction and mining equipment, testified that biologic expenses represent the fastest-growing segment of its $600 million in annual US healthcare spending. Caterpillar's spending on biologics has risen 45 percent since 2004, Banwart testified.
Recognizing the threat generic biologics pose to manufacturers' bottom line, a Friedman Billings Ramsey analyst this week slashed revenue projections for Amgen Inc.'s Epogen, an anemia drug that can cost $10,000 per year. The drug's patent expires in 2013 .
"Even if watered down, legislation sponsored by Representative [Henry] Waxman is threatening to biologics makers with looming patent expirations," FBR analyst Jim Reddoch wrote in a research note. "We calculate that Epogen is worth roughly 25 percent less with generic biologic competition than without."
Diedtra Henderson can be reached at dhenderson@globe.com.
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WASHINGTON -- European regulators told a Congressional panel today that some biological drugs -- such as insulin and human growth hormones -- are simple enough to produce in generic versions, but others are too complex to be safely duplicated.
Generic versions of certain biologics have been allowed in Europe for the last four years, but approval came only after manufacturers conducted rigorous human clinical trials. European regulators recommended today that the United States adopt the same standards.
The testimony came during a Senate Health, Education, Labor and Pensions committee that is considering a bill to permit United States regulators to approve generic versions of biologics, drugs based on living organisms and cells.
Too much flexibility for generic manufacturers in Europe would have "spread suspicion" that the generic biologic products were unsafe, said Nicolas Rossignol, who is responsible for implementing the European Commission's legislation governing generic biologics. Rossignol testified from Brussels.
Senator Edward M. Kennedy, who chairs the committee, called biologic drugs "miracle medicines" that can come at a steep price to the healthcare system tens to hundreds of thousands of dollars annually per patient. Americans spent an estimated $60 billion on such products last year, according to IMS Health, a healthcare information company, compared with $53 billion in 2005.
Generics that are chemical equivalents to conventional drugs save Americans at least $10 billion per year. The Food and Drug Administration, however, lacks the legal ability to approve generic versions of biologics.
Kennedy, Democrat of Massachusetts, said such legislation should be "led by the science," while protecting patient safety and valuing the investments made by innovator companies.
Opponents of the current measure, including Senator Orrin Hatch, Republican of Utah, say it lowers safety standards and could imperil patients. Hatch cosponsored legislation that speeds to market generic versions of conventional drugs. He favors requiring that prospective generic biologic manufacturers test their drugs in humans before approval. Hatch also supports establishing patient registries to track side effects that may not occur until years after patients start using a product.
"What we need to do is keep working to get the best legislation," Hatch said.
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WASHINGTON -- Federal regulators charged with approving generic versions of the world's most expensive drugs should follow the lead of their cautious European counterparts, according to Senator Edward M. Kennedy . In Europe, requirements for approval are tailored to the complexity of an experimental drug and can include clinical trials that cost millions for generic manufacturers to conduct.
Tomorrow, the Senate Health, Education, Labor and Pensions Committee, which Kennedy chairs, will hear opposing views about legislation that would give the Food and Drug Administration the ability to approve generic versions of biologic drugs. Name brand biologics, which are based on living organisms, help patients suffering from serious ailments but can cost thousands of dollars per month.
On average, each day the FDA approves one new generic version of a conventional drug that is the chemical equivalent of its branded counterpart and can cost 60 percent less.
But the FDA says it lacks the regulatory power to approve generic versions of expensive specialty drugs, such as insulin, human growth hormone, and biologic therapies that treat multiple sclerosis and anemia . One estimate, disputed by the biotechnology industry, suggests that generic competition for just those four classes of specialty drugs could save $71 billion over the next 10 years .
A bill cosponsored by New York Democratic senators Charles E. Schumer and Hillary Clinton, a member of the Health, Education, Labor and Pensions panel, would open the door for lower-cost generic biologics to enter the US market. Such business leaders as General Motors Corp. and Aetna Inc., which face staggering increases in their healthcare spending due to specialty biologics, support the legislation.
"We have a responsibility to expand the horizons of medical science in every responsible way possible so people can live longer and fuller lives," Kennedy said yesterday in a statement. "Our goal in legislation should be to enable companies to invest in new medical breakthroughs while doing all we can to cut costs for patients and protect safety."
Following Europe's example would give generic manufacturers guidance about the type of analyses and clinical trials needed to gain FDA regulatory approval, according to a Kennedy staffer.
Kennedy's willingness to require generic-biologic manufacturers to conduct clinical trials is a stance endorsed by local biotech leaders, including Genzyme Corp. and Biogen Idec Inc. Both companies sell brand-name biologic drugs and could face competition from generic versions.
"The public safety is at stake. The public confidence is at stake. You can't force the issue. You have to do it carefully," said Henri Termeer, Genzyme chief executive.
Termeer expects US regulators ultimately will follow the European example, even if it slows approval times for generic biologics. "It's very carefully considered wording where every protein -- because every protein is different -- is considered by itself."
Tim Hunt, a Biogen Idec spokesman, is among those who argue that waiving clinical trial requirements for manufacturers of generic versions of biologics is "lowering the bar on drug safety. To achieve safety, you're probably going to need to run clinical trials," Hunt said.
Schumer and other congressional backers of the bill object to the biotechnology industry's criticism.
"Safety is not an issue here. It's a bogus issue brought by those who wish to prevent change," Schumer said last month when the bill was introduced in the House and Senate. "We can be very smart about how we do this. We want the science to take the lead."
Still, if the bill that passes both houses of Congress follows Europe's lead, it could add millions to the cost of developing generic biologics.
For instance, to satisfy European regulators reviewing its application to sell a generic version of an anemia treatment, Hospira Inc. was asked to conduct a number of analytical studies, preclinical studies, and clinical trials comparing its product to branded versions.
The approval requirements were "quite burdensome," said Terry Gerrard, president of TLG Consulting Inc. and a former FDA reviewer who handled biologic approvals.
Because generic drugs have narrower profit margins than branded versions, a shift toward costly clinical trials could have a chilling impact, said Jim Bianco, chief executive of Cell Therapeutics Inc. The Seattle company recently established a spin-off company, Aequus BioPharma Inc., to develop a technology that could speed commercialization of generic biologics.
"If the hurdles are too high, even though the markets are attractive, then one looks at the whole time-value-money consideration for where else they make their investments," Bianco said.
Diedtra Henderson can be reached at dhenderson@globe.com.
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Members of Congress on both sides of the aisle and in both chambers are taking the first steps toward revising the 1984 law that established standards for the federal government's approval of generic drugs and its granting of patent extensions for brand- name prescription drugs.
The law, the Drug Price Competition and Patent Term Restoration Act, was intended to strike a balance between promoting innovation (by guaranteeing makers of brand-name drugs a certain number of patent years) and ensuring that consumers have timely access to lower-cost generic medicines (by guaranteeing makers of generic drugs that those patents would eventually end). It is commonly called the Hatch-Waxman Act after its authors, Sen. Orrin G. Hatch, R-Utah, and Rep. Henry A. Waxman, D-Calif.
Since the law was enacted 16 years ago, the pharmaceutical industry has changed greatly. Cutting-edge but expensive "biologics," such as human growth hormones, are now prevalent, and generic medicines are in wider use. So in recent months, Hatch and Waxman have separately met with various players in the pharmaceutical industry and with consumer groups who want the law updated.
Thus far, there is little consensus among lawmakers or other interested parties about which areas of the pharmaceutical industry should benefit from any congressional changes to the act, which are probably years off. Still, the matter of escalating consumer costs appears to be an emerging theme.
"We need to look for ways to make (medicines) more affordable," Sen. James M. Jeffords, R-Vt., chairman of the Senate Health, Education, Labor, and Pensions Committee, said in an interview. "The cost of prescription drugs to our people is too high, and we have to do something to get them down."
Waxman believes that several areas of the 1984 law need attention. In a speech to an industry group in late January, he said most pressing is "the need to stop-once and for all-the numerous efforts to obtain patent extensions benefiting a few at the expense of the many. I am talking about efforts to secure special patent extensions and special extensions of market exclusivity, in direct contravention of the Waxman-Hatch Act and its underlying purpose."
One such case involves legislation sought by seven drug companies-including Schering-Plough, the makers of Claritin, the nation's top-selling allergy drug -that would allow them to seek patent extensions from the Patent and Trademark Office. Supporters of the proposal argue that delays by the Food and Drug Administration in approving the marketing of Claritin wasted several years of its patent. A patent extension would delay the introduction of cheaper generic versions of Claritin into the marketplace.
Hatch, for his part, has boasted that the Hatch-Waxman Act increased the market share of generic prescription drugs from 19 percent in 1983 to 43 percent in 1996. The Congressional Budget Office has estimated that generic substitutions were saving consumers $ 8 billion to $ 10 billion a year by 1994. All the while, says Hatch, investment in pharmaceutical research and development has grown.
"These statistics help explain why many believe that my 1984 legislation successfully balanced the interests of American consumers in obtaining both innovative and affordable medicines," Hatch said in a statement late last year. "However, I believe it is timely for Congress to revisit this issue so consumers may continue to receive quality pharmaceuticals at affordable prices."
As the debate unfolds, generic drugmakers are looking for assurances that brand-name patents expire when they are supposed to. They complain that their brand-name counterparts have resorted to unfair tactics to extend patents. Generic industry representatives also want the ability to produce generic alternatives to biologics. Current law makes it difficult, if not impossible, for them to do so.
The budding biologics industry isn't very worried about potential competition from generic drugmakers. Biologics are extremely complex and difficult to produce because they involve the growth of a biological, rather than synthetic, component.
Instead, the biologics industry wants the Hatch-Waxman Act reopened because it is seeking the guarantee of enough patent years to make its investments worthwhile. The industry lost $ 5 billion last year, and officials at the Biotechnology Industry Organization, the Washington association representing companies that develop and produce biologics, have complained that it is difficult to attract investors because of uncertainties surrounding the patent process.
The Biotechnology Industry Organization welcomed a patent reform bill enacted last year. The new law guarantees that the Patent and Trademark Office, which calculates patents based on the date of application, will assign 17-year patent terms, unless the patent-seeker itself attempts to delay the process.
But then the FDA, which must approve a drug or biologic before it can be marketed, takes over the process. There are no guarantees on how long the FDA's review will take, which is something that the biologics and pharmaceutical producers would like to rectify.
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