Biotech Strategy Blog

Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Cancer Immunotherapy

Posts from the ‘FDA’ category

Juvenile rheumatoid arthritis (JRA) is a disease that results in chronic joint inflammation, and is the most common rheumatology disease in children.

The American College of Rheumatology classifies juvenile RA into 3 subtypes, one of which is systemic JRA.  The news that the FDA just approved tocilizumab (Actemra®) from Roche for pediatric systemic JRA (SJRA) is therefore good news for several reasons:

1. Very few drug companies obtain pediatric indications for their drug since registration trials are more routinely undertaken with adult patients.

2. In several adult phase III clinical trials, tocilizumab was also shown to delay joint damage as measured by ACR20, ACR50 and ACR70 responses.  An ACR 20 response requires a patient to have a 20% reduction in the number of swollen and tender joints.

If you look at the adult phase III clinical data that has been published for the AMBITION, LITHE, OPTION, TOWARD, RADIATE studies, what is noticeable to me is the high percentage of patients across the studies who had an ACR20 response within 24 weeks (70%, 56%, 59%, 61%, 50%); in all cases a significant improvement over placebo plus methatraxate or other disease modifying anti-arthritic drug (DMARD).

Source: Roche data on adult phase III trial results

However, it’s clear from the above data that fewer patients had deep responses e.g. ACR50, ACR70.  Tocilizumab is a treatment option for those who have failed previous RA therapies, and while not a cure, can provide symptom relief and improve joint function in those suffering from moderate to severe RA.

According to the Roche press release, data from the pediatric study known as TENDER, showed that 64/75 children (85%) of children with SJRA experienced an ACR30 improvement.  Given the fact the drug is already approved for adult use, and has extensive phase III trial data, a small pediatric sample size is not unexpected.

Summary:

A pediatric approval is good news, as all too often pharma and biotech companies neglect this market.  I plan to write more in future posts about RA drugs in development as I think this is a market that may continue to evolve new treatment options over the next few years.

The 102nd Annual meeting of the American Association for Cancer Research (AACR) ended yesterday in Orlando, and it was only the diehards who kept going till the last session of the last day for an update on “Novel Androgen Receptor Antagonists.”

As I mentioned in an earlier post, there is a lot of excitement in the prostate cancer field at the moment with three new therapies approved last year (cabazitaxel, sipuleucel-T, denosumab), and more expected over the next two years (abiraterone acetate, MDV3100, cabozantinib/XL-184).

What I took from the AACR session I attended, is that there are also other products in the pipeline that are worth watching.  Below is a list of some of the products that were mentioned. It’s not intended to be a comprehensive review of the prostate cancer landscape, only my notes and thoughts on some of the new products that the speakers touched upon.

Abiraterone Acetate: The postive phase III trial results were reported last year at ESMO and ASCO GU, and the approval of this drug is currently being considered by the FDA.  Approval is expected shortly, and possibly in time for launch at the forthcoming annual meeting of the American Urological Association (AUA) meeting in Washington, DC.

Abiraterone (brand name Zytiga) inhibits the enzymes (17-alpha hydroxylase and C17, 20 lyase) responsible for adrenal androgen formation.

The phase III results were impressive in very sick patients who were close to the end of their lives in very advanced disease.  Overall survival increased from 10.9 to 14.8 months in the second line chemotherapy setting post docetaxel.  It’s expected that the results will be more dramatic pre-chemotherapy.

Once the FDA approval is obtained, it’s hard to see how oncologists will not consider abiraterone instead of cabazitaxel in the second-line chemotherapy setting.  An easily taken pill with fewer less side effects may be a more convenient option for elderly or frail men with prostate cancer.  Abiraterone’s approval will not be good news for sanofi-aventis.

I also expect we will see significantly off-label usage of abiraterone pre-chemotherapy by urologists as they seek to maintain hormone-sensitivity in their patients after several lines of anti-hormonal therapies.  There is a phase III trial ongoing in this setting that is expected to show promising data by the end of the year.

However, it’s a good strategy to come market as soon as possible to provide wider access to patients in need, and the post-docetaxel second line setting allowed the overall survival benefit to be shown before the pre-chemo data would be available.

However, what I learned at the meeting is that abiraterone acetate may not be the best product in the long term.  Currently it requires the corticosteroid, prednisone, to be given at the same time to attenuate the mineralocorticoid effects.  Questions that were raised in the AACR session about long-term treatment with abiraterone included, “Must a corticosteroid be given concurrently?” and “What about hypertension?”

Other questions remain, such as possible development of resistance to abiraterone. Often the first drug to market is not the best, and it’s possible that second generation new products in the pipeline may be better than abiraterone and delay the time to resistance further.

However, what abiraterone does have is first mover advantage and depending on the pricing strategy adopted by Johnson & Johnson, the ability to capture market share earlier.  It will be interesting to see what happens with this drug, but it’s certainly an exciting time for patients with prostate cancer.

TAK-700: This drug from Takeda/Millennium is a more potent inhibitor of C17α-hydroxylase than abiraterone.  One of the panelists at AACR believed that TAK-700 “may in the long run surplant abiraterone acetate due to less need for mineralocorticoids.” TAK 700 entered phase III clinical trials late last year.

MDV3100:  This drug is being developed by Medivation/Astellas and is also in phase III trials, with data expected by the end of this year or early 2012.  It has a high affinity for the androgen receptor. However, what came across in the AACR presentation by Howard Scher, was his view that the second compound developed by Charles Sawyers, ARN-509 may be better than MDV3100.

ARN-509: This drug from Aragon Pharmaceuticals is in phase I/II clinical trials and is definitely one to watch.  As Dr Scher pointed out, ARN-509 is more potent than MDV3100 and I expect we will see publication of more data on ARN-509 in the near future.

If you are interested in prostate cancer, AACR are offering webcasts and podcasts of scientific sessions this year.  Further information can be found on their website.  AACR have also announced a scientific special session on “Advances in Prostate Cancer Research” from February 6-9 2012.  It’s certainly an interesting and exciting time in this field as new products become available, something that is likely to make a real difference to how this disease is treated.

 

In a unanimous decision, the United States Supreme Court decided yesterday that pharmaceutical and biotechnology companies may have an obligation to disclose adverse events to investors, even if the data is not statistically significant.

I previously discussed the case of Matrixx Initiatives, Inc. v. Siracusano on this blog and correctly predicted that the Supreme Court would uphold the decision of Court of Appeals for the Ninth Circuit.  The result is a valid securities class action fraud claim that can now go to trial, or more likely, a financial settlement will be worked out.

You can read more on the background to this case in my previous post, but at issue was whether Matrixx Initiatives, Inc. (Matrixx) mislead investors by not disclosing reports that some consumers had lost their sense of smell (anosmia) after using Zicam Cold Remedy.   Despite product liability lawsuits, complaints from consumers and medical scientists drawing the company’s attention to previous studies linking zinc sulfate (contained in the Zicam nasal gel) to loss of smell, Matrixx continued to be optimistic to investors about the company’s performance and prospects.

In the November 2003 Form 10-Q filed with the Securities and Exchange Commission (SEC), the company made no disclosure that two lawsuits had been filed over alleging use of Zicam had caused a loss of smell.

The decision in Matrixx Initiatives, Inc., v. Siracusano case has major implications for investor relations, public relations and corporate communications departments of publicly traded companies within the biopharmaceutical industry.

Under U.S. Securities and Exchange Commission (SEC) Rule 10b-5 companies have an obligation to disclose material facts related to statements that are made that could impact the purchase or sale of stock i.e. you have to provide all the information necessary to avoid a statement being misleading.  This does not mean that companies have to share all material information about their products, they control what they say, but what they say has to contain all the material facts necessary for it to be truthful and accurate.

Say a major pharma company issues positive press releases at a major medical congress announcing great clinical trial results, while at the same time the Data Monitoring Committee (DMC) is meeting to terminate the study because the drug has too many adverse events.  My reading of the Matrixx decision is that the company cannot make the positive statements without including the information about their concerns about adverse events.  In those circumstances they might be better off not making the positive press releases, rather than potential misleading investors into buying stock on the back of this data, when the drug may end up being terminated shortly afterwards.

As Justice Sotomayor states in her opinion, “the materiality of adverse event reports cannot be reduced to a bright-line rule.” Matrixx Initiatives, Inc. v. Siracusano, 563 U.S. ___ (2011) (slip op., at 1-2).

The presence or absence of statistical significance is not the key factor as to whether an adverse event is material or not.

“A lack of statistically significant data does not mean that medical experts have no reliable basis for inferring a causal link between a drug and adverse events.”

(slip op., at 12).   As Justice Kagan noted in her questioning at oral argument and Justice Sotomayor picked up in her opinion, “[t]he FDA similarly does not limit the evidence it considers for purposes of assessing causation and taking regulatory action to statistically significant data.” (slip op at 13).

Justice Sotomayor goes on to conclude that reasonable investors may also base their decision on non-statistically significant data.  The challenge that the industry now faces is determining what information is “material” and needs to be disclosed.  A bright-line rule of statistical significance would have made this easy.

Companies, their investor relations and public relations agencies are now faced with the question of what is “material”, and what is not.  The guidance the court offers is that:

“assessing the materiality of adverse event reports is a “fact-specific” inquiry that requires consideration of the source, content, and context of the reports.”

(slip op., at 15, citations omitted).  The Court notes this does not mean that “pharmaceutical manufacturers must disclose all reports of adverse events” only those for which “a reasonable investor would have viewed the nondisclosed information as having significantly altered the total mix of information made available” (slip op., at 15, citations and quotation marks omitted).

So should all adverse events be reported?  That’s one possible way to avoid deciding what’s material, but Justice Sotomayor, clearly states that this is not the standard to be applied. She states,

“mere existence of reports of adverse events which says nothing in and of itself about whether the drug is causing the events – will not satisfy the standard.”

(slip op., at 16). What is needed is some link between the adverse event and the drug that suggests possible causality, what Justice Sotomayor describes as a “contextual inquiry.”  She goes on to say that it is this contextual inquiry that can come from other sources or reports.  In the Matrixx case this would have come from the filing of lawsuits, the concerns of academics about causal links, consumer complaints, the presentation of a scientific poster etc.

“This contextual inquiry may reveal in some cases that reasonable investors would have viewed reports of adverse events as material even though the reports did not provide statistically significant evidence of a causal link.”

(slip op., at 16).  The conclusion from the Matrixx case is that publicly listed companies should be very careful of the information that they tell the market.  As Justice Sotomayor notes:

“Even with respect to information that a reasonable investor might consider material, companies can control what they have to disclose under these provisions by controlling what they say to the market.”

(slip op., at 16).  Whatever information is given to the market e.g. investor presentations at conferences, press releases, press briefings or SEC reports, the information should not be misleading through the omission of material facts.

What the Matrixx decision does is include adverse events as possible material facts, even those adverse events that have not been proved to be causal, or have reached statistical significance.  The conclusion being that disclosure of adverse event data may need to be included, if the omission of this information could impact the decision making of a reasonable investor.

In practice, clinical departments and medical affairs will need to be more closely involved with investor relations, and judgments will have to be made as to what information is disclosed.  Any time a judgment is required, there are likely to be differences in opinion as to what is “material” or not.  Prudent companies should consider sharing more information rather than less, but how to do this in a way that does not overburden investors will be the challenge.

 

After I wrote my previous blog post about the emerging biotechnology region around Austin, TX, one of the comments I received was about the importance of networking opportunities within a cluster or region.

So I am pleased to have been invited to a medical technology-life science networking event in New York City (NYC) organized six times a year by Ted King of Saddlerock Advisors, Wendy Brown of Merrill Lynch and John Lieberman of Perelson Weiner.

The event, later today, has a format of a featured speaker and presentations by three emerging companies that provides them with the opportunity to network and showcase their technology, new drugs or medical devices to investors, industry partners, academics and researchers.

This evening there is a presentation on the proposed changes to the FDA’s 510(k) clearance process for medical device approval.  This is the route by which the majority of medical devices come to market by showing they are comparable to an existing approved or marketed product.

The three featured companies include BioView (an Israeli technology company involved in cell imaging and automation of genetic testing), Cel-Sci (a Virginia based biotech company that has as immunotherapy product in development about to enter a global phase III clinical trial in head and neck cancer) and PatienTech (a company that develops elastic-sheet, pressure sensing systems that can be used with medical devices).

It will be interesting to see who attends, and whether the presentations by the companies are what I consider to be the typical investor “puff and fluff” presentations, or whether there is any meaningful discussion of science, marketing strategy and new product development.

Following on from my blog post last week that discussed the use of iPads and other tablet computers in clinical trials, MIM Software have just received FDA 510(k) clearance to market their iPhone and iPad medical imaging app in the United States. This is the first such approval by the FDA, and the app will be sold in Apple’s itunes store.

This new mobile radiology application will allow physicians to review medical images on their iPhone and iPad.  The FDA in their press release indicate that it is not intended to replace full work stations, but to provide the ability to view images and make diagnoses when a workstation is not readily available.

The FDA reviewed luminance, image resolution quality, and results from demonstration studies with radiologists that showed that images could be safely interpreted for diagnostic purposes under appropriate lighting conditions.

What is more, using software from MIM, the images can be further analyzed and distance measurements made.

The ability to have wireless access to medical images will be particularly useful to physicians working remotely, in emergency situations and in clinical trial networks where the central imaging review facility may not be local.

As the screen resolution of iPad’s and other tablet computers increases, perhaps we will see advanced visualization software available on the iPad?  It is certainly an area where innovation is taking place, and one that I think will impact clinical research in the biotechnology industry before too long.

In a case that is set to have major impact on the biotechnology industry, the United States Supreme Court heard oral argument yesterday in the case of Matrixx Initiatives Inc. v. Siracusano. The question presented to the court is:

“Whether a plaintiff can state a claim under § 10(b) of the Securities Exchange Act and SEC Rule 10b-5 based on a pharmaceutical company’s nondisclosure of “adverse event” reports even though the reports are not alleged to be statistically significant.”

You can find all the briefs and documents related to the case on the excellent Scotusblog. website.  A transcript of yesterday’s oral argument has been published on the U.S. Supreme Court website.

At issue is whether knowledge of possible adverse events is material information that must be disclosed to investors, even if not statistically significant.  The biotechnology industry argue that such a requirement would impose an unreasonable burden upon them and could lead to drugs not being developed.

Matrixx Initiatives is a pharmaceutical company that sells OTC cold remedy products including Zicam Cold Remedy Nasal Gel that was recalled in 2009 following an FDA determination that the product was not safe.  During the period 2002- 2004 the company became aware of reports that use of its nasal gel was linked to a loss of smell, anosmia.  The company did not announce this information to investors until after several law suits were filed and several notifications of a possible link between the smell loss and Zicam nasal gel had been made to it.

Shareholders subsequently brought a class action law suit alleging that the company and its executives violated the Securities Exchange Act of 1934 by failing to disclose material information.  The District Court granted Matrixx’s motion to dismiss the complaint and action for a failure of the shareholders to make a claim.  The U.S. Court of Appeals for the 9th Circuit in a June 2009 opinion reversed this decision, and the U.S. Supreme Court granted a writ of certiorari to hear an appeal.

Rule 10b-5 of the Securities and Exchange Commission (SEC) states that:

“It shall be unlawful for any person directly or indirectly…. to make any untrue statement of a material fact or to omit to state a material fact …in connection with the purchase or sale of any security.”

In the Matrixx case, the shareholders claimed that the failure of the company to disclose information regarding the possible link between Zicam and anosmia was the omission of a material fact.  In other words had they known that there was a possibility that Zicam could cause a loss of smell, they would not have bought shares in the company at the price they paid for them or would have sold them.

What is the standard for deciding if something is material?  It is “…whether there is a substantial likelihood that a reasonable shareholder would consider the fact important” TSC Industries, Inc. v. Northway, Inc., 426 U.S. 438, 449 (1976).

The District Court dismissed the complaint against Matrixx on the basis that the reports of anosmia were not statistically significant, and therefore not material.

The U.S. Court of Appeals for the 9th Circuit reversed the trial court’s decision, based on the U.S. Supreme Court decision in Basic Inc. v. Levison, 485 U.S. 225, 236 (1988) that held “[t]he determination [of materiality] requires delicate assessments of the inferences a “reasonable shareholder” would draw from a given set of facts and the significance of those inferences to him.”

The 9th Circuit rejected the use of a bright line test of statistical significance as the standard to apply in deciding whether data was material or not.  Instead, the Court of Appeals engaged in a fact-specific inquiry and concluded that between 2002 and 2004 there was sufficient information to make a plausible claim that should be put to a jury.

In reversing and remanding the district court’s dismissal of the shareholders action, the 9th Circuit concluded that “the District Court’s reliance on the statistical significance standard to conclude that Appellants failed to establish materiality is inconsistent with the Supreme Court’s rejection of bright-line rules and its emphasis on having materiality determined by the trier of fact.”

The case is now on appeal to the United States Supreme Court, and several leading biotechnology associations have filed amicus briefs seeking to have this decision over-turned.  Bay Bio argue that the non-disclosure of statistically insignificant adverse event reports does not make a company’s statements about its products or earnings fraudulent under the securities laws.  Bay Bio raises the concern that failure to disclose isolated reports of adverse events, even if not medically or statistically significant, will lead to potential liability.  In their amicus brief, Bay Bio argue that:

“If left standing, the Ninth Circuit’s rule will require companies to make boilerplate disclosures of adverse event reports virtually every time that they make a statement, along with a disclaimer that the company does not believe that such reports have any bearing on their statements. Such an information dump will add nothing to the mix of information already available to reasonable investors. At the same time, such disclosures will needlessly cause consumers to avoid using safe, beneficial drugs.”

I am not sure that I agree with this position.  Are adverse events material information – yes?  If only statistically significant data mattered, then scientific papers and presentations of clinical trial results would not include non-significant information.  In fact, an adverse event may be significant in one trial and not in another, based on the sample size, power of the study, patient selection criteria and clinical trial design.

I am not persuaded that only statistically significant data are material to physicians, investors and patients.

As to the burden on the industry, I am also not sure that I accept the dark picture painted that making adverse event data available will be an unreasonable burden, in light of existing reporting mechanisms.  One has to remember that Zicam nasal gel, the product in question in this case, was being sold to consumers – it was not an investigational product.  Looking at the totality of the information about a potential serious adverse event such as loss of smell, one has to believe that after several reports and law suits, there was some obligation to let investors and consumers know.

What’s the outcome in the U.S. Supreme Court – clearly to grant a writ of certoriari, there are at least four justices who wish to hear this case.  Whether they have a pro-business view that requires this case be overturned or a pro-consumer view that favors full disclosure of information to investors, I have no crystal ball as to the outcome.

Justice Kagan in oral argument was razor sharp, noting that:

“the FDA takes action all the time as to drugs, they force the withdrawal of a drug from the market, they force relabeling of a drug on the basis of findings that are not statistically significant. Now, clearly in those cases the market has a right to know the very things that are going to make the FDA take action against a product and that are going to severely affect the product’s value to the company. Not statistical significance there.”

She pointed out to Jonathan Hacker, Esq. the attorney for Mattrix that he was:

“suggesting a test for what counts as material, which is statistically significant, a test that the FDA itself doesn’t use when it thinks about what it should what should regulate.”

Justice Kagan clearly was on good form and went on with the following hypothetical, how would you answer it?

“There’s a pharmaceutical company and it comes out with its first and only product, it’s 100 percent of the sales, and it’s a new contact lens solution.  And it sells this product to many, many, many hundreds of thousands of people.  And most of them use this product with no adverse effect whatsoever, but there are ten cases where somebody uses this product and they go blind.  Three of those ten cases, the person had to borrow a contact lens from a friend, only used it in one eye, they go blind only in that one eye.  This is not statistically significant.  There is no way that anybody would tell that you these ten cases are statistically significant.  Would you stop using that product and would a reasonable investor want to know about those ten cases?”

My answer would be “yes” I would want to know and even though not statistically significant, this is material information that I would want to know about before it was talked about on “Good Morning America” and everyone then dumped their stock.

So at the risk of alienating those in the biotechnology industry who think otherwise, my money is that the court will uphold the 9th Circuit opinion and not impose a bright line rule that materiality is governed by statistical significance.  We can expect a decision towards the summer on a case that may lead to major changes in how adverse events are reported by pharmaceutical and biotechnology companies.

The race to bring a biosimilar version of Sanofi-Aventis’ low molecular weight heparin, Lovenox® (enoxaparin sodium), to market had three players, Momenta Pharmaceuticals in partnership with Sandoz, Amphastar Pharmaceuticals and Teva.

The winner was Momenta/Sandoz who (as mentioned in a previous post) recorded $292 million of sales in 69 days post launch.   As reported by the Wall Street Journal, Amphastar are now suing the FDA alleging the agency acted arbitrarily in delaying its imports of raw heparin.  There certainly seems to be no love lost between Amphastar and the FDA, who earlier this year alleged a conflict of interest between Janet Woodcock, the Director for the Center for Drug Evaluation and Research (CDER) and Momenta as a result of the collaboration that identified the contaminant in chinese heparin that killed patients in 2008.  Following an FDA investigation, Woodcook was cleared of any conflict of interest but announced she would not participate in the biosimilar approval decision.

In the run up to the approval, the FDA visited the manufacturing facilities for all three companies. Afterwards the status of the Amphastar application became less certain. Unlike Amphastar, both Teva and Sandoz had prior experience of obtaining FDA approval for biosimilar products.

Given the amount of money at stake, its easy to see why Amphastar are unhappy. However, alleging conflicts of interest and arbitrary practices does not exactly win friends and influence people.  I am sure the FDA have a credible factual basis for their decision making, in which case Amphastar is unlikely to get anywhere, other than generate negative publicity for themselves.  Others may differ in that opinion, and if you want to read a legal analysis of the Amphastar complaint, the FDA Law Blog’s post is worth reading. It also has a link to the actual complaint filed.

The more interesting question is when is the FDA going to approve the Teva biosimilar version of Lovenox®? When this happens, Sandoz’s first mover advantage will come to an end and further price erosion is likely. According to Reuters, analysts predict this may happen before the end of 2010.

Update: Amphastar gains FDA approval for generic Lovenox

As reported by Ed Silverman on Pharmalot (September 19, 2011), “Amphastar Pharmaceuticals has finally won approval to sell a generic version of Lovenox

2 Comments

The news, reported by Bloomberg, last week that generic companies may be subject to stricter FDA standards in order to show therapeutic equivalence is good news for the biotech industry and consumers.

Generic companies have a pretty easy ride in obtaining product approval, and I’ve long been convinced that the formulation of a brand, and what makes it work can include the so called inactive ingredients and how it is put together.   I know of many people who have experienced side effects with generics that they don’t have with the branded product.

For this reason, branded generics from the original manufacturer have the ability to retain some market share in the face of generic competition.  Sandoz, the generic arm of Novartis uses this strategy to good effect with many mature products.   However, if companies instead want to try and maintain a premium priced brand and not adapt to the entry of generics, then they will find their market share erodes extremely fast. Not only is brand market erosion fast with generic drugs, but with biosimilars too.

As reported by Reuters, sales of generic enoxaparin sodium injection, Momenta’s copy of Sanofi’s anti-thrombotic, low molecular weight, heparin sold as “Lovenox” were $292million in the third quarter of 2010. Sandoz markets enoxaparin on behalf of Momenta. They launched the product on July 23, and achieved  $292 million of sales in 69 days. With annual sales forecast to be over $1billion, the biosimilar will be a blockbuster and make a significant dent in the $2.9 billion sales of Lovenox in 2009.

The Boston Business Journal reports that Sandoz/Momenta have captured 60% market share already, which is not good news for Sanofi-Aventis and may explain their desire to make acquisitions such as Genzyme to make up for this loss.

Biosimilars that are fully substitutable for the original product, look likely to erode brands extremely fast.  Momenta’s success is good for the biotechnology industry and highlights the future market opportunity from development of biosimilars.

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