Last week, I blogged on the issue of generic biologics: should companies that make vaccines, monoclonal antibodies, cell therapies, etc. get 12 years of data exclusivity before competing companies begin offering generics? Or should they be held to the same standard as makers of drugs, who get five years of exclusivity?
Looks like the U.S. Senate is caving in to pressure from Pharma and the Biotech industry by opposing the Obama’s “compromise” position: the Senate bill urges 12 years. But in today’s New York Times, journalist Andrew Pollack suggests the exclusivity debate might not matter in the end: most biologics are protected by patents beyond 12 years after FDA approval. Meaning: short exclusivity periods advocated by various public interest groups would have no material impact on development of generic biologics, because generics would be prevented by patents. The article contains a graphic showing that patents on several leading biologics products extend well beyond 12 years.
So is this just a symbolic debate? I think not (disclaimer: I am not a health care economist!). Towards the end of the article, Pollack acknowledges that the exclusivity debate might matter where patents do not provide strong protection. That’s a crucial issue for biologics. Intellectual property law around biologics is notoriously unstable and uncertain. And owing to their complex composition, generic manufacturers might plausibly argue that their products are biosimilar while not infringing patents. Advocates of the 12 year policy will argue that longer exclusivity is necessary to entice investors who might otherwise worry that lead products will not withstand patent challenges. Advocates of the shorter policy (like myself) will argue that we owe it to present day patients and their families to take that risk. (photo credit: sortofbreakit 2008).
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Jonathan Kimmelman. "Orange Light on Generics" Web blog post. STREAM research. 22 Jul 2009. Web. 28 Apr 2024. <https://www.translationalethics.com/2009/07/22/orange-light-on-generics/>
APA
Jonathan Kimmelman. (2009, Jul 22). Orange Light on Generics [Web log post]. Retrieved from https://www.translationalethics.com/2009/07/22/orange-light-on-generics/
Today, Lancet ran an editorial asking whether Phase 0 trials will become a “platform for drug development.” The editorial responds to the first published ‘phase 0’ study, this June, in Journal of Clinical Oncology (Kummar et al). These studies involve delivering very small quantities of a new drug to test its properties before giving biologically active levels to patients. They promise to improve the efficiency of drug development by screening drug candidates before they are tested in larger, riskier phase 1 trials.
The Lancet editorial notes the potential of phase 0 studies, but raises questions about their ethics: “no therapeutic benefit can be conferred by the small doses in a phase 0 study, and while taking part, patients are not allowed to enrol in a trial with therapeutic intent.” As I have argued in Journal of Law, Medicine, and Ethics, however, the former issue is a red herring: normal phase 1 trials routinely, and deliberately, deliver levels of drug that are too low to cause therapeutic response. Moveover, whether phase 1 trials in themselves have “therapeutic intent” is debatable.
There are, of course, many ethical concerns surrounding phase 0 studies. Chief among them is whether patients understand their nontherapeutic nature, and whether results are publicly reported (I predict that if phase 0 methods are taken up by the private sector, many results will languish in filing cabinets). But effective engagement with ethical issues in phase 0 cancer studies requires, in my view, that we take a more careful look at whether “therapeutic intent” is really the litmus that determines whether a study pursued in patients is ethical. (photo credit: w i n t e r t w i n e d 2009)
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MLA
Jonathan Kimmelman. "Phased by Phase 0?" Web blog post. STREAM research. 17 Jul 2009. Web. 28 Apr 2024. <https://www.translationalethics.com/2009/07/17/phased-by-phase-0/>
APA
Jonathan Kimmelman. (2009, Jul 17). Phased by Phase 0? [Web log post]. Retrieved from https://www.translationalethics.com/2009/07/17/phased-by-phase-0/
Gene transfer, cell transplantation, monoclonal antibodies, enzyme replacements, tissue engineering all have great potential to improve health care. But will we be able to afford them? Various economists have shown that a large proportion of health care cost inflation is attributable to new technology, and the significant costs of development and production for drugs involving genes, cells, and large proteins- what regulators call “biologics”- provide grounds for concern that new biotech products will break the bank.
Questions about the affordability of biotech drugs are heating up in DC as Congress takes a look at generic biologics. Under current policy, there are no regulatory pathways for approving generic versions of biologics. This effectively means that companies that develop biologic drugs have a monopoly on them long after patents expire. Representative Henry Waxman, who previously sponsored legislation creating a pathway for generic drugs, is presently spearheading efforts to establish a way of reviewing and approving generic biologics as well.
The policy and economic issues here are profoundly complex, and much of the debate about legislation revolves around the issue of “data exclusivity.” Briefly, this refers to the period after drug approval during which generic competitors are barred from using data from the innovator’s clinical trials to apply for generic approval. In the U.S., for example, generic drug companies cannot file applications with FDA until five years after the new drug is approved by FDA. The aim of exclusivity is to reduce the economic impact of free rider generic companies that depend on trial data collected by the innovator.
The biotech industry, and many economists, argue that much longer periods of data exclusivity are required for biologics. They argue that without longer exclusivity periods (like 12 to 14 years), companies will have insufficient incentive to develop new biologics. Consumer advocates often argue otherwise, citing the mouth dropping costs associated with using many new biologics.
It remains to be seen who will prevail in this debate, but Waxman and the Obama administration appear inclined toward the consumer advocates, with the former urging a 5 year period, and the latter endorsing a “compromise” of 7 year exclusivity.
At stake is not simply question of markets and economics, but also one of ethics. Namely, should how should health care economies balance the need of current patients (who can ill afford expensive biologics) against those of future patients (who might benefit from greater innovation should exclusivity periods be extended)?
Sound ethical analysis must discount benefits accruing to future patients and consider the justice implications of excluding current patients from otherwise available treatment so that others in the future might benefit from new drugs. If implemented, the Obama administration’s plan for generic biologics promises to reduce an important hurdle in ensuring an equitable future for cutting edge therapies. (photo credit: shazam791, a true generic brand, 2008)
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MLA
Jonathan Kimmelman. "Generic Biologics" Web blog post. STREAM research. 14 Jul 2009. Web. 28 Apr 2024. <https://www.translationalethics.com/2009/07/14/generic-biologics/>
APA
Jonathan Kimmelman. (2009, Jul 14). Generic Biologics [Web log post]. Retrieved from https://www.translationalethics.com/2009/07/14/generic-biologics/
A few further observations from the American Society of Gene Therapy Meeting…
A recurrent theme in this blog is the frequency with which novel research fields encounter safety problems that confound laboratory predictions. One presentation at the 2009 ASGT meeting brought this point home.
Recall my entry on May 12 discussing various refinements to retroviral gene transfer that are aimed at reducing risk of malignancy. Researchers have postulated that HIV-derived lentiviral vectors might not cause the same leukemia-inducing mutations as retroviruses, and RAC recently passed a favorable judgment on a lentiviral vector gene transfer protocol for X-SCID.
How confident can we be that lentiviruses will not trigger leukemias? Some indication is provided in a May 2009 review by John Rossi in Molecular Therapy. It concluded “overall, the results of these [safety] analyses [of lentiviral vectors] are highly encouraging…” but “clearly, more careful analyses… are warranted in appropriate animal models.”
At ASGT, researchers from France reported preliminary results from a phase 1 trial testing lentiviral vectors in patients with beta-thalassemia. The study involved two patients. Though no malignancies have been detected, tests in one patient showed signs that some cells were repopulating the patients blood much faster than others (what researchers call “clonal dominance”). This is a worrisome signal, as it might indicate a premalignant state.
The lessons here are not that lentiviral vectors are unsafe (we don’t know whether this will lead to a malignancy), or that such vectors shouldn’t be used in human beings (we can’t say anything yet about the risk-benefit balance). Instead, I think the lesson is: in novel research areas, be very wary of anyone who makes emphatic claims that their system provides safe harbor. Expect the unexpected. (photo credit: dark matter, 2005)
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MLA
Jonathan Kimmelman. "Safe Harbor? Leukemia, Gene Transfer, and Lentiviral Vectors" Web blog post. STREAM research. 23 Jun 2009. Web. 28 Apr 2024. <https://www.translationalethics.com/2009/06/23/safe-harbor-leukemia-gene-transfer-and-lentiviral-vectors/>
APA
Jonathan Kimmelman. (2009, Jun 23). Safe Harbor? Leukemia, Gene Transfer, and Lentiviral Vectors [Web log post]. Retrieved from https://www.translationalethics.com/2009/06/23/safe-harbor-leukemia-gene-transfer-and-lentiviral-vectors/
Last year’s “big ticket” item at ASGT was results from the first three patients in two gene transfer trials testing nearly identical products against a rare form of congenital blindness, Leber’s Congenital Amaurosis (LCA). I previously blogged (here and here and here and elsewhere) on the controversial decision to move the intervention into children, given the novelty of the intervention, that the trial is primarily a safety study, and that blindness is not a fatal condition.
Today, Jean Bennett of University of Pennsylvania presented an update on the first three patients (previously reported in New England Journal of Medicine) plus results on the next three patients. Here’s a synopsis. The first three patients continue to show dramatic improvement in objective measures like pupillometry (that is, their pupils are responding to flashes of light in a way that does not normally occur in patients with this form of blindness), and they show signs of improved vision.
The next three patients were children eight years or a bit older. Bennett showed dramatic footage of a child unable to find his way through a maze when using the uncorrected eye, and navigating a maze with relative ease with the corrected eye. She also showed data indicating retinal function in regions of the eye receiving vector. Improvements in vision were greater with the children than in the previous cohort- which she chalked up to the fact that retinal tissue was not as degenerated in younger patient-volunteers. The team did not observe any gene transfer-related adverse events.
The other two LCA trials were conspicuously missing from the meeting. Rumor has it that the Penn team has been far more successful recruiting patients with this rare disorder. Bennett flashed a slide at the beginning of her presentation showing that patients had been accrued from several continents- North America, Africa, Europe, and elsewhere. Patients in the second cohort, according to Bennett, are begging to have their second eye dosed. (photo credit: Ferran 2009).
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MLA
Jonathan Kimmelman. "The Vision Thing: Update on LCA" Web blog post. STREAM research. 30 May 2009. Web. 28 Apr 2024. <https://www.translationalethics.com/2009/05/30/the-vision-thing-update-on-lca/>
APA
Jonathan Kimmelman. (2009, May 30). The Vision Thing: Update on LCA [Web log post]. Retrieved from https://www.translationalethics.com/2009/05/30/the-vision-thing-update-on-lca/
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MLA
Jonathan Kimmelman. "Clonal Trouble" Web blog post. STREAM research. 29 May 2009. Web. 28 Apr 2024. <https://www.translationalethics.com/2009/05/29/clonal-trouble/>
APA
Jonathan Kimmelman. (2009, May 29). Clonal Trouble [Web log post]. Retrieved from https://www.translationalethics.com/2009/05/29/clonal-trouble/
One of the most exciting and intellectually compelling talks thus far at the American Society of Gene Therapy meeting was Pedro Lowenstein’s. A preclinical researcher who works on gene transfer approaches to brain malignancies (among other things), Lowenstein asked the question: why do so many gene transfer interventions that look promising in the laboratory fail during clinical testing? His answer: preclinical studies lack “robustness.”
In short, first-in-human trials are typically launched on the basis of a pivotal laboratory study showing statistically significant differences between treatment and control arms. In addition to decrying the “p-value” fetish- in which researchers, journal editors, and granting agencies view “statistical significance” as having magical qualities- Lowenstein also urged preclinical researchers to test the “nuances” and “robustness” of their systems before moving into human studies.
He provided numerous provocative examples where a single preclinical study showed very impressive, “significant” effects on treating cancer in mice. When the identical intervention was tried with seemingly small variations (e.g. different mouse strains used, different gene promotors tried, etc.), the “significant effects” vanished. In short, Lowenstein’s answer to the question of why so many human trials fail to recapitulate major effects seen in laboratory studies is: we aren’t designing and reviewing preclinical studies properly. Anyone (is there one?) who has followed this blog knows: I completely agree. This is an ethical issue in scientific clothing. (photo credit: Rick Eh, 2008)
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MLA
Jonathan Kimmelman. "Mice- Three Different Ones: Towards More Robust Preclinical Experiments" Web blog post. STREAM research. 29 May 2009. Web. 28 Apr 2024. <https://www.translationalethics.com/2009/05/29/mice-three-different-ones-towards-more-robust-preclinical-experiments/>
APA
Jonathan Kimmelman. (2009, May 29). Mice- Three Different Ones: Towards More Robust Preclinical Experiments [Web log post]. Retrieved from https://www.translationalethics.com/2009/05/29/mice-three-different-ones-towards-more-robust-preclinical-experiments/
This year’s annual meeting of the American Society of Gene Therapy is in San Diego. I’ve been to several interesting talks thus far, and plan to post entries on a few. For now, here’s an overview of some major (or some not so major) clinical developments in gene transfer that are being reported at this meeting.
1- Last year, I predicted that the first gene transfer applications were nearing licensure. Not so fast. Because of concurrent sessions, I was unable to attend the entire talk given by Robert Shaw of the British biotech company Ark Therapeutics. Ark has developed a gene transfer approach, Cerepro, that uses adenovirus to treat malignant glioma (which is one of the most aggressive types of cancer). Ark recently applied to the European drug regulatory authority, EMEA, for registration of Cerepro. Why not FDA? Dunno (though the speaker stated that the review standards are more or less the same). The data behind the product are less than earth shaking. According to information available over the web [proviso- these data are from August 2008], the pivotal phase 3 study of Cerepro showed only a 42-day increase in survival for patients in the active drug arm. And the product caused “increases” in hemiparesis, aphasia, and fever.
2- Another somewhat discouraging indication of the challenges in reaching licensure for gene transfer products was a session titled “late stage industry clinical trials.” To me, late stage means phase 3. But three talks centered on phase 1/2 studies, and none presented phase 3 results. The first talk was given by Ceregene on their Parkinson’s disease product Cerepro. The product did not show any significant advantage over sham for their primary endpoint.
3- Last year, the “buzz” at ASGT was the preliminary results from three studies testing AAV vectors for a form of congenital blindness, LCA. I also discussed the somewhat ethically controversial decision to move this study into children. I will look forward to attending Jean Bennett’s talk on Friday; her abstract reports that her LCA study has enrolled “9 children and young adults” ranging from age 8 to 26 years. The abstract claims improvement in “subjective and objective” measures of vision. To be continued… (photo credit: slack12, 2008)
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MLA
Jonathan Kimmelman. "ASGT in San Diego" Web blog post. STREAM research. 28 May 2009. Web. 28 Apr 2024. <https://www.translationalethics.com/2009/05/28/asgt-in-san-diego/>
APA
Jonathan Kimmelman. (2009, May 28). ASGT in San Diego [Web log post]. Retrieved from https://www.translationalethics.com/2009/05/28/asgt-in-san-diego/
Are government bureaucrats keeping dying patients from getting access to possibly life saving drugs? That’s one way to read Margaret Talbot’s story in the Sunday New York Times (“Fighting for a Last Chance at Life.” May 17, 2009). Talbot describes how mother Kathy Thompson sought access to an unlicensed therapy Iplex for her Amyotrophic Lateral Sclerosis (ALS)- afflicted son, Joshua. The drug, Iplex, was not licensed by FDA for use against ALS, and an almost identical drug had failed two randomized controlled trials in patients with ALS.
Buoyed by anecdotal patient reports on web forums, Thompson sought compassionate use access from the FDA and was rebuffed. She ultimately engaged the Washington Legal Foundation to appeal FDA’s rejection of Thompson’s request for the drug. FDA relented, allowing the drug maker to run a trial of Iplex– recouping all costs from enrolled patients (about $100k/year).
There are a number of troubling features in this story. First, the article (or, at least Thomspson) makes FDA out to be a bunch of heartless bastards. Some, like the Washington Legal Foundation, view FDA’s stringency as an affront to the “civil liberties of American Business” (to paraphrase Haley Barbour). But let’s remember that, for over a half a century, FDA has played a critical role in public health by keeping unproven drugs out of the pharmacy. Grants of compassionate use seriously weaken the ability of the state to collect evidence of a drug’s safety and efficacy, because they make enrollment in clinical trials much more difficult. So there need to be some pretty compelling policy reasons- backed by persuasive evidence- to grant exemptions.
Second, the article states “Many are Campaigning for the chance to be treated with drugs whose safety and effectiveness is not yet known.” While Iplex itself hasn’t been tested against ALS, its active ingredient has been tested in two large randomized controlled trials. Both failed to show any advantage over placebo.
Third, there’s the business of allowing desperate patients to “buy” their slots in the trial approved by FDA. For starters, it’s hard to imagine that a trial that included only “several dozen patients” is going to be of any use in measuring safety or efficacy (the two failed studies involved about 180 and 300 patients). As well, there is something unseemly about a “compassionate use” exemption that is priced at $100K.
ALS is an awful disease, and I feel for people like Thompson and her son. Surely, more and better care and research are needed for ALS sufferers. But where’s the compassion in a program that ministers only all to the most wealthy and politically connected? More importantly, where’s the compassion in undermining a system that ultimately protects us all from clinics that prey on the desperation of patients, and companies that sell unsafe, ineffective, and extremely expensive drugs? (photo credit: Monster 2007)
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MLA
Jonathan Kimmelman. "A Cure? "Compassionate Use" and Drug Regulation" Web blog post. STREAM research. 17 May 2009. Web. 28 Apr 2024. <https://www.translationalethics.com/2009/05/17/a-cure-compassionate-use-and-drug-regulation/>
APA
Jonathan Kimmelman. (2009, May 17). A Cure? "Compassionate Use" and Drug Regulation [Web log post]. Retrieved from https://www.translationalethics.com/2009/05/17/a-cure-compassionate-use-and-drug-regulation/
Who says the British Press isn’t all yellow? “Doctors have begun trials using gene therapy to treat patients for cystic fibrosis.” So proclaims an April 19 story in the Guardian (“Cystic fibrosis to be treated by gene therapy technology”). “Cystic fibrosis gene cure closer,” reads a Februrary 2009 BBC headline.
“‘We are not curing the condition,’ stressed scientist Dr. Deborah Gill. ‘We will merely be halting the erosion of patients’ lung function.'”(photo credit: Lisabuddka 2008)
Last week, I blogged on the issue of generic biologics: should companies that make vaccines, monoclonal antibodies, cell therapies, etc. get 12 years of data exclusivity before competing companies begin offering generics? Or should they be held to the same standard as makers of drugs, who get five years of exclusivity?
