Pharma’s Cutting Edge

After I had fnished reading the recent Supreme Court decision in Riegel v. Medtronic and some news reports describing the supposed implications of the decision for pharma, I was confused.  Were the implications for pharma product liability cases broad and profound or narrow and limited?  Certainly, the upcoming Wyeth Supreme Court case will have its own implications for pharma, but, in the meantime, I turned to my colleague Greg Glass, editor/owner of the Paragraph Four Report, to lend his opinion to the Court’s Medtronic decision.  Here’s what he said:

As for the [Medtronic]  case, you have to read it very narrowly. It appears that the gist of the lawsuit was that the plaintiff did not have much to go on in suing Medtronic. The product [apparently] was contraindicated for the use for which it was administered to the poor guy, and the balloon was filled to 10 atmospheres, rather than the maximum [recommended] pressure of 8.  So, it appears that there was not much product liability theory to go on. ([The situation would have been different] if the facts instead were that the product was used for its intended use and the balloon ruptured at 4 atmospheres).

So, the plaintiff, being “creative,” asserted the product failed to meet certain design and manufacturing standards.

The point of the law [MDA], and the FDCA for that matter, was to create a uniform approval and safety standard. For example, what would happen if Texas passed a law that required new drugs to have three controlled studies before the product could be sold in Texas? So, the idea is to have one set of rules — federal law — to control these things.

[Following this ruling], you can still sue under state laws in state courts for product liability cases — but those laws can’t create higher manufacturing and approval standards than what federal law creates. Federal courts are harder to get into and usually don’t hear the standard product liability cases.

That seems pretty clear to me.  If the device doesn’t work as it’s supposed to, according to the FDA, plaintiffs still have the opportunity to sue in state court under product liability laws.  But if the device is pushed beyond its recognized (labeled) limits, as the facts supported in this case, plaintiffs can’t sue in state court using a state law that creates a tougher standard for the product than the FDA recognizes.

Avastin Distribution Change - Open Letter

I read today’s WSJ Health Blog on Avastin thinking that Genentech had appeased eye specialists by maintaining distribution of Avastin to compounding pharmacies, but after reading the above open letter, I’m confused about Genentech’s actions in the recent past and about what it’s planning to do in the near future.  Take a look and let me know if you share in my confusion.

The decision we communicated [to cease Avastin distribution to compounding pharmacies] was not made lightly. In fact, it was guided by our company’s strong commitment to take actions that are scientifically and clinically sound and in the best long-term interest of patients, while at the same time adhering to government regulations and remaining mindful of the retinal community’s views.

The above open-letter snippet suggests that Genentech was motivated by their concerns around the safety of Avastin formulated for intravenous delivery being delivered ocularly.  They make this explicit later:

Genentech’s decision was not motivated by a desire for increased profits. We did not and do not expect that this change in policy toward compounding pharmacies will lead to any increase in LUCENTIS® (ranibizumab injection) sales. Further, we expect Avastin to be available and that physicians will continue to prescribe it for ocular indications.

So far, so good.  Genentech is making a logical argument.  Essentially it’s saying that, like Hippocrates himself, Genentech aims to first do no harm.  Fair enough, although I think it’s disingenuous of a for-profit company to imply that an important decision can be divorced from a business case, but I’ll leave that for a future discussion.

Then we get the news that FDA had inspected Genentech’s manufacturing facilities (just when, relative to the company’s compounding-pharmacy decision, we’re not told), and Genentech reacted:

…[W]e destroyed four batches of Avastin deemed unsuitable for use in the eye due to a higher visual inspection standard. (These lots would have been entirely suitable for its approved use as an intravenous cancer medication.) The action resulted in the loss of more than 350,000 vials of Avastin with a market value of more than $200 million.

Now I’m lost.  Why would Genentech have to destroy $200 million of Avastin stock intended for use as a cancer therapy (albeit used off-label for other uses, included ocular uses) to appease FDA inspectors?  Is Genentech saying that FDA mandated that Genentech produce a product capable of withstanding the same visual-inspection standards required of ocular drugs and that Genentech relented to this mandate without fighting it?  Is that what Genentech is saying?  Okay, let’s say that’s it for arguments sake.  What happens next?

The letter implies that sometime after this self-imposed drug destruction, Genentech made its compounding pharmacy decision and soon after that met with key opinion leaders to revisit the decision (N.B. no mention was made of FDA’s involvement at this KOL meeting).  Genentech communicates publicly after this KOL meeting that it will continue to supply Avastin to compounders until at least January 2008 and maybe longer if FDA approves. 

In contrast to what was earlier implied by the juxtaposition of the FDA manufacturing/packaging audit and destruction of drug, this latter sequence of events suggests that Genentech’s Avastin destruction was voluntary, not FDA imposed.  Why else would Genentech be able to decide unilaterally to continue supplying Avastin to compounding pharmacies–without FDA approval to do so–beyond November, the original date of its distribution cessation?  If FDA had ordered destruction of Avastin they would have also, it would seem, had to approve continuation of its supply to compounding pharmacies.  Yet, no mention is made of such approval.  Indeed, Genentech states that it will continue shipment of drug to compounding pharmacies after January only with FDA approval, again suggesting that FDA is having some say in how Avastin is distributed (or packaged for distribution to compounding pharmacies).

So, I’m left with a bunch of questions that leave me wondering what really happened here and what is going to happen come February 2008:

What did FDA actually find during its audit and what specifically prompted the destruction of a large amount of Avastin intended for use in oncology?  Was the destruction voluntary or FDA-mandated? What alternatives to destroying the drug were considered?

What changes to manufacturing/packaging were made following destruction of the drug, and how will such changes affect distribution to compounding pharmacies? 

Is an FDA ruling on manufacturing/packaging changes both necessary (as implied in the open letter) and sufficient for Genentech to extend distribution of Avastin to compounding pharmacies beyond January 2008?

Is Genentech planning to change the cost of Avastin for compounding pharmacies?  Will there be distinct ocular-specific and oncology-specific formulation/packaging?

When we get some answers to these questions, I’ll post an update.

Disclosure:  I have no equity or other financial stake in Genentech or its direct competitors.

Last week Byron Dorgan, Senator for North Dakota and colleagues, including Olympia Snowe, Republican from Maine submitted legislation to the U.S. Senate that would amend the Food, Drug and Cosmetic Act to provide for drug importation by non-manufacturing companies and individuals into the United States from registered exporters in other countries.  For individuals, importation would be limited to drugs originating from Canada, whereas registered institutional importers would be able to import drugs from Canada, Europe, Japan, Australia and New Zealand.  A companion bill was introduced into the House by Representatives Rahm Emanuel (D-IL) and Jo Ann Emerson (R-MO). 

The AARP promptly supported the bills, which are variants of very similar legislation that was first introduced into Congress in 2003 and re-introduced in 2004 and again in 2005.  Is the fourth time a charm?  Well, with a newly Democratic Congress it might be, although poltical pundits, which I do not claim to be, seem to believe that there will not be enough votes to avoid an assured veto by President Bush should the legislation make it to a vote and be passed by both houses. 

I know that pharmaceutical companies and FDA have both argued against such legislation, ostensibly because they believe such export/import will leave U.S. consumers with a drug supply tainted with counterfeit medicines.  The bill’s sponsors believe that they have adequately addressed such concerns in their legislation. 

I think manufacturers and FDA have a legitimate point.  I don’t believe that current technology and oversite resources, even if boosted by money flowing into FDA from fees collected from importers, will suffice to keep the supply of drugs on store shelves at the status quo level of quality.  My opinion is subject to change in the near-term, particularly if some clever technologies are deployed to tackle the tough problem of tracking medicines.  RFID was once portrayed as a panacea, but it is showing itself to be something less. 

In prinicple, however, I support legislation providing for regulated trade of medications across international borders.  Generally speaking, I favor relatively unimpeded international trade of nearly all manufactured goods and see no compelling reason to prevent cross-border trade of pharmaceuticals once a drug-supply equivalent to the U.S. status quo can be reasonably assured.

The $64,000 question pharma would like to have answered is:  What will happen to U.S. drug prices if this or similar legislation becomes the law of the land?  The Congressional Budget Office was asked in 2003 to make an estimate of cost savings to taxpayers, and they chose European parallel imports as the basis for making the estimate.  Of course, they had to lay all sorts of assumptions on top of the European analog to make it work as a basis, but it’s as good a basis as any, which is to say it’s not very good. 

The real problem with interpreting CBO’s estimated drug expenditure reductions of 0.5% for Years 1 and 2 post-implementation and 1% for the Years 3 through 9 is that their report doesn’t actually show how they arrived at their figures for expenditure savings.  Doh! 

Nevertheless, it’s clear that any savings to consumers will be modest.  Personally, I think consumers in the U.S. won’t save a dime, because other governments have no interest in creating a supply shortage in their homelands that could drive domestic drug prices upwards.  They’ll do what they must, including banning drug exports to the U.S. to avoid it.  The most popular drugs (i.e the most expensive drugs) will be banned from export first.  Limited export supply will drive up the prices exporters charge for all non-banned drugs.  Importers wil have no choice but to pass along these higher prices, owing to their already razor-thin margins, leaving wholesalers with a not-so-cheap supply, etc. 

Eventually, the bulk of the export-import business goes away, as everyone realizes that it’s not such a hot business to be in, leaving a handful of very efficient exporters and importers who survive but make almost no impact on consumer drug spending.  That is…I guess that’s what would happen.

So if I were advising PhRMA, I’d say fear not this legislation.  The marketplace efficiencies will reveal that higher drug prices in the U.S. are not primarily due to restricted importation.  But I’d also say, you’re not crazy for worrying about the quality of the U.S. drug supply.  Sure, coming out against the bill for whatever reason makes the industry look like a gang of lying, hypocritical profit-mongers, but hey, you should be used to that by now.  Fact is, importation as proposed could harm the U.S. drug supply.  Work behind the scenes to get that part of the bill fixed, then, as a wise doctor once said, stop worrying and learn to love the bomb. 

This press release from FDA cracking down on compounding practices got some broad coverage this past week. Compounding, the selective creation of new drugs using bulk drug substance or drug products by pharmacists, is a legal activity when done for an individual patient with special drug needs, in response to a valid prescription. FDA maintains a web site that describes what pharmacists may and may not do to be in compliance with compounding rules and regulations. FDA has long been wary of “compounding” activities that resemble large-scale manufacturing and distribution of drug products, as are alleged for the three pharmacies given warning letters. In response to the FDA warning, RoTech announced it would cease production of the compounded products and would switch 30,000 patients to brand-name drugs. Look for more FDA warnings in the weeks ahead, with “biodentical” hormone compounders probably the next to be targeted.

Pharma’s Cutting Edge Vol. 4 Number 3 - March 2006

Review of EMEA Biosimilars Guidelines

Last month EMEA (the European Medicines Agency) released final guidelines containing details of clinical, nonclinical and quality expectations for biosimilar protein therapeutics (aka generic biologics, aka biogenerics, aka follow-on biologics or proteins). These guidelines were themselves as expansion of the general guideline released in September 2005 and of two earlier documents, a note for guidance containing nonclinical and clinical issues (December 2003) and a quality guideline (also December 2003). All of these documents are conveniently located on a single page on the EMEA website.

As of today, two biosimilar proteins have been recommended for approval by the CHMP (Committee for Human Medicinal Products, the human medicines technical component
within EMEA), both somatropins (growth hormones): Omnitrope (Sandoz) and Valtropin (BioPartners). Based on CHMP’s specific guidelines for insulin and G-CSF biosimilars, we can infer that registration dossiers have been submitted for biosimilars in these categories (potentially adversely affecting primarily Novo Nordisk and Hoffman-La Roche, respectively). Other widely used therapeutic proteins that are susceptible to biosimilar competition in Europe today, owing to patent expiration, are erythropoeitin (Eprex, Janssen) and interferon-alpha2b (IntronA, Schering-Plough). We can expect CHMP guidelines for biosimilars for these drugs soon. In addition to Sandoz and BioPartners, companies that stand to gain in the near-term from the EMEA’s actions are listed in this PharmaWeek article.

In the U.S., FDA has been considering its own guidance for follow-on biologics (biosimilar) developers and manufacturers for some time. It’s hinted that a draft guidance will be forthcoming this year. Sandoz isn’t holding its breath waiting for FDA to get its act together on this issue. It sued FDA in September last year, asking the Court to rule that FDA must act on its application for Omnitrope now, one way or another. FDA asked the Court to dismiss the suit in November. So far, no further action has occurred. In the meantime, U.S. observers can learn from the CHMP’s guidelines, as it is likely that scientific guidance from FDA will be similar.

My goal in this issue is to provide an overview to these recent guidelines, focusing on the key issues. I’ll discuss them in the order of general guideline, nonclinical, clinical and quality and then touch on the specific product guidelines. I realize that this is a long post, but it’s far shorter than the original guideline documents, and it isn’t every year that a completely new category of drug marketing authorization comes to fruition.

General Guideline

Scope

• Theoretically covers all biologics, including vaccines, blood-derived products, antibodies, etc.

Application of “similar biological medicinal products approach:”

• differs from the standard generics approach as it is based on a comparability exercise rather than a demonstration of bioequivalence
• is more likely to be applied (and to be successful with) highly purified biologicals, such as recombinant proteins
• must fulfill quality, safety and efficacy requirements (discussed later)
• results in products that are similar but not in generic equivalents, necessitating the need for clear product identification to facilitate pharmacovigilance.

Choice of reference product

• Active substances must be similar (structure and function).
• Reference product must be approved in the Community (meaning the countries embodied by the EMEA).
• Pharmaceutical form, strength, and route should be the same; differences will have to be justified.

Note on immunologicals (e.g. vaccines)

• Vaccines and allergens are complex and unlikely to be well characterized molecularly.
• They will therefore consider them on a case-by-case basis.

Note on blood or plasma-derived products

• Such products have complex and variable physico-chemical, biological and functional characteristics.
• Therefore, such products must satisfy safety and efficacy requirements as found in BPWG “new products” guidance note and related documents.

Other biologicals

• Cell and gene therapy products will be considered in the future.

My take away: Although the similar biological approach is potentially relevant to all biological medications, in fact, the current guidelines are intended primarily for development of biosimilars referenced to well-characterized recombinant protein therapeutics, including monocloncal antibodies.

Nonclinical Guideline

General (applicable to clinical as well)

• Within a biosimilar MAA (marketing authorization application) dossier, each indication for use will be considered separately.
• Efficacy and safety for each indication will either have to be demonstrated or an extrapolation from one indication to another justified.

Scope (applicable to clinical as well)

• Covers biosimilar applications for recombinant proteins only and only when no changes are introduced in the manufacturing process.

Nonclinical study program

• Studies should be done prior to clinical studies.
• Should be designed to detect response differences between the reference and biosimilar, not just responses per se.
• In vitro receptor-binding or cell-based [binding] assays should normally be done.
• In vivo studies should measure the pharmacodynamics relevant to clinical use.
• At least one repeat-dose toxicity study should be conducted.
• Toxicokinetics should include antibody titers, cross reactivity and neutralizing capacity
• Other routine types of tox studies are NOT normally required.

Clinical Guideline

General

• Test product should be studied clinically using the final manufacturing process, unless justified and supported by additional data.
• Clinical comparability is done in stages, much like a traditional program.

Pharmacokinetics

• Clinical comparability pharmacokinetic (PK) studies should NOT necessarily mimic a standard comparability design that focuses on absorption and bioavailability. Rather, such studies should also include exploration of clearance and elimination.
• Choice of design must be justified and careful attention should be paid to issues such as elimination half-life.
• The acceptance range to conclude clinical comparability should be defined and justified.

Pharmacodynamics

• The pharmacodynamic (PD) effects should be compared in a population where “possible differences can best be observed.”

When will PK/PD studies alone suffice to determine clinical comparability:

• when PK of the reference product is well characterized
• when PD properties (e.g. binding to receptor) of the reference product are well characterized
• when the PK/PD relationship of the reference is well characterized
• when a PD marker exists and the PK/PD relationship using the marker is well known.
• when the PD marker is a well characterized surrogate of the clinical outcome of interest
• when the dose range is chosen to demonstrate assay sensitivity (see ICH E10 for a discussion of assay sensitivity)
• when the PK and PD margins defining clinical comparability are defined and justified a priori. Read the rest of this entry »
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