Resources regarding ethics of gene editing

Recently, two resources have become available regarding gene editing and the issues raised by it.

First, the National Academies of Science, Engineering, and Medicine have made available an archive of its February 22 webinar about human gene editing.  The home page for the Academies’ human gene-editing initiative is here.  A link to the archived webinar is here.  The slides can also just be viewed here.

Second, Issue 1 of Volume 24 of the journal The New Bioethics is dedicated to human gene editing.  The entire issue, or individual articles from it, are available online for purchase, or for viewing if you have access through an academic institution.  Article titles deal with, for example, differentiating gene editing from mitochondrial transfer, comparing ethical issues with gene editing vs embryo selection, and “selecting versus modifying” to deal with disabilities.

I have not been through these materials in any detail, yet.  The webinar looks a smidge promotional, co-sponsored as it was by the Biotechnology Industry Organization (BIO).  But it also recommends the Academies’ report on the status of human gene editing, and summarizes key recommendations, which include limiting efforts (at least for the present!) to editing “somatic,” or, if you will, “adult” cells to make them into cellular therapies for recognized diseases.  This is well within the existing ethical and regulatory regime governing clinical research and treatment development, as opposed to the deeply problematic prospect of heritable gene editing, or attempts to edit genes for human enhancement, both of which the report and the webinar (at least the slides) counsel that we NOT rush into.  The New Bioethics articles look thoughtful and worth reviewing, which I hope to do (and comment on) in the near future.

Doctor-assisted death: resisting the slippery slope

The New England Journal of Medicine has two new “op-ed”-style pieces raising concerns about extending physician-assisted suicide (PAS) from people with end-stage terminal illness to people who may express a desire to die because of (non-terminal) mental illness.  (Regrettably, both require subscription access.)  PAS in these cases is being exercised in Belgium and the Netherlands, and is being considered in Canada

In one article, the authors label PAS for psychiatric patients “misguided public policy,”   Although patients may be suffering terribly from, say, severe depression, they may be victims of “distorted cognition” that leads them to see their lives as worthless.  This, the authors argue, is a manifestation of the mental disease—so, in a sense, it’s not “healthy” or “real” (my words, not theirs).  In essence, the patient is not somehow mistaken about his suffering—rather, it’s potentially treatable.  Unless in some cases it’s not, I suppose, in which case it’s not clear how the authors would resolve that.  Oh, and in the absence of universal health insurance (a problem that the Dutch and Belgians and Canadians all avoid, they allow), some miser might see PAS as a convenient way to save a few bucks—or quite a few, for that matter.

Some suicidal psychiatric patients may indeed make “rational and autonomous” (the authors’ phrase, not mine) decisions for PAS, but doctors might make diagnostic mistakes and “let other patients slip through.”  Must such mistakes be accepted, as a sort of “collateral damage” for an otherwise desirable policy?  No, the authors say; to allow PAS for psychiatric patients contradicts “physicians’ commitment to preserving life and preventing suicide.”  To this last point, I might offer an “Amen.”

In the other article, a Dutch doctor argues that there, and in Belgium, the PAS regime is simply too lax.  For PAS to be ethical, he argues, it must be a last resort.  But no such safeguards are in place there, and, indeed, eligibility for one form of treatment—deep brain stimulation—requires a more stringent evaluation than PAS does.  The author of this article would permit PAS for psychiatric patients not only if all treatment options had been considered, but “only if the patient had not refused a reasonable treatment option” (emphasis mine).

So much for autonomy, I guess.  Back to a (welcome?) paternalism that recognizes the doctor’s calling is first to care for and preserve life?

The second author concludes that PAS should be considered only in parallel with “recovery-oriented care,” to ensure “that there is a treatment advocate involved, [that PAS is not] used as an escape for an overwhelmed physician, and [that] the focus of care [is not] narrowed down to death.”

Um….yipes?

Reviewing the ethics of paying human research subjects

Sometimes it is both necessary and proper to pay a person to participate in a clinical trial, of a drug or some other medical intervention, or a data-collection study, or something else that involves people.  An article in this week’s New England Journal of Medicine reviews many of the relevant ethical issues.

A link to the article is here.  Correction to initial post:  subscription or purchase does appear required.

Why pay somebody to be in a trial?  The main reasons are to reimburse them for unavoidable expenses, to compensate them for time that would not otherwise be required in the course of standard medical care or normal life, and, indeed, to get them to participate in the first place.  In cancer medicine, where I’ve worked, the subjects are cancer patients who are generally not paid to participate; they usually are willing to do so in the hope of possible benefit, plus, often, a sense of altruism.  But most drugs have their first human testing in healthy volunteers, to begin to identify potential safety concerns and understand how, and how rapidly, the drug is eliminated from the body.  In those cases, the research subjects are almost always paid, sometimes substantially.

Such payments are not necessarily unethical, as long as they are not too big.  If they are, then they could create an undue influence to participate.  That would upset the balance of benefits and risks and compromise true informed consent.  By well-accepted ethical standards for research on human subjects—many of which are codified in regulation—the risks to human subjects must not be excessive, must be avoided or mitigated to the extent reasonably possible and commensurate with the goals of the research, and must not exceed the foreseeable benefits of the research, either to the individual subject or to society overall (e.g., in the form of important medical knowledge), or both.

Payment to a subject is not considered a benefit in and of itself, but should be “neutral” to the benefit/risk assessment.

There’s no hard and fast rule about paying subjects—no single standard “fee schedule,” so to speak.  Rather, each ethics board reviewing a study must also review and approve the amount and timing of payments to subjects.  Again, such payments should be high enough to respect the subject’s contribution to the research, but not too high so as to give them incentive to participate when maybe they should not.  Also, it’s a general principle that payment should be in installments; generally, no more than 10-15% of the total should be held back to the very end of the study.  Why this last point?  Because it’s also a principle that subjects can opt out of a study at any time, but if they think “I have to stay in to the bitter end to get paid,” that could pressure them too much.

Note, BTW, that such pressure is not the same as coercion, which by definition involves a threat, and does not apply to this payment question.

Also, payments must be appropriate so that subjects don’t get a wrong idea about the potential value or efficacy of an experimental drug, or that they might be induced to try to be in more than one study at once.  You might be surprised how significant that last risk is.  In my past IRB work, we just to worry about “professional subjects” who make some level of living by going from one research study to another.  More than one at once means getting two or more drugs at once that probably ought not to be combined, willy-nilly.

And of course, the potential for economic exploitation of low-income individuals must also be considered and respected.

The NEJM article really doesn’t break new ground but is a helpful review for those interested in essential research ethics.  The FDA has also provided guidance, which can be reviewed here.

Fertility with frozen eggs: not a sure thing

In case you didn’t see it, the Washington Post has this story about how more women are trying to improve their overall chances of having a baby—particularly in the later reproductive years of their 30’s and 40’s—but success is far from certain.  Human oocytes (eggs) are fragile things, and it was not until recent years that freezing techniques developed to a point that would allow the eggs to survive being frozen and, some time later, thawed (the “freeze-thaw” cycle).  Then, they would be fertilized in the lab, by in vitro fertilization, and implanted into the womb of the would-be mother.

As the article points out, women are born with their entire endowment of eggs, which become less likely to be successfully fertilized and develop into a healthy baby as they, and the woman, age.  Hence a woman’s inexorably declining fertility, particularly from their mid-30’s on.  Freezing eggs for later use is increasingly popular, if one can afford it, or if employers offer it as a perk, as some do, to their female employees.

It’s still expensive, and success appears to depend on the age of the woman (and eggs) at their harvest, and the number harvested and kept in frozen storage.  One must use the qualifier “appears,” because, as the article also points out, reliable statistics are not being kept.  The not-so-subtle implication is that the fertility “industry” wants to sell the process but would rather not know that the ultimate success rate could be as low as, or lower than, the 50-60% rate quoted by New York University.

Clear implications: better data and more transparency are to be desired, and there appear to be at least some remaining biologic limits, strong if not absolute, to reproductive freedom.  Beyond that, as I opined in May of 2013 (fairly bluntly, I do confess) are the radical implications for our concepts of parenthood and begetting children, and for turning said procreation into just plain old, quality-controlled, fully artificial creation.  Things haven’t gotten quite so absolute, yet.  But better quality control of egg freezing and the outcomes, if possible, would be a move in the direction of more artificial reproduction.

It’s a good article from the Post.  Too much to try to do justice to here.  Read the whole thing.

Update on clinical studies of human gene editing

The January 22 edition of The Wall Street Journal carried an article the essential message of which was, “the Chinese are ahead of us in gene editing.”  Specifically, more human clinical trials are active in China than in the US using gene editing in some form to treat people with specific diseases.  Some of these trials use the “hot, new” CRISPR-Cas9 approach to gene editing.  Almost all of the active ones are in China, although one has recently been approved by regulators to begin in the U.S., at the University of Pennsylvania.  That one appears not yet to be recruiting patients.  In most of these “CRISPR” trials, cells are removed from a patient’s body, altered in the laboratory to make them more likely to treat the disease in question (in this case read: attack a cancer), and injected back into the patient.  They are thus variations on a 30-or-so-year-old approach of using cells that have been modified in some way to treat cancer.

The difference here is that the cells have their genes edited, and that raises potential safety risks, such as, what happens if the wrong genes are “edited,” and the altered cells go nuts and do something undesirable?  Because of this, human trials of gene editing in the U.S. are closely regulated, including having to pass scientific and safety review by the “RAC” (that’s for “Recombinant DNA Advisory Committee,” in case the acronym made any of you think of the Spanish Inquisition…then again, I have had researchers who have had to go through it suggest that the analogy is apt…).

The RAC was established back in the late 1970’s when drugs started being made with recombinant DNA, and trials of gene therapy using genes inserted into viruses were conducted.  A famous case of that work going awry raised concerns about oversight, and slowed things down substantially.  And as it stands now, the U.S. regulatory process for this work is cumbersome.  In China, not so much—a local ethics review board looks at a proposal, and off they go.  The WSJ makes it sound like informed consent for the Chinese studies may be a bit thin, too.  U.S. experts are quoted as saying not that we need less regulation, but that they (the Chinese) need more, to bring them back to our speed.

Perhaps so.  My point here is that this work is going on.  Examples like those cited here seem to me to fall under the existing regulatory regime for human trials, and don’t pose the same sort of ethical issues as the potential for inherited gene edits—that is, editing embryos and babies.  That’s a different kettle of fish.

One Chinese CRISPR trial appears not to alter cells outside the body, but actually try to administer the genetic material to make an edit to a cervical cancer-causing gene.  That poses similar safety concerns to other gene therapy approaches, including some with “zinc finger” editing technology, like a currently-active U.S. study to treat hemophilia, a disorder in which someone has a genetic flaw that makes them susceptible to excessive bleeding and the goal is to repair the offending gene.

In considering this work, I think it’s important to distinguish use of the gene-editing approach for incremental steps to treat human disease, like the cell therapy approaches, or true “gene therapy” approaches in which a “corrected” gene is administered to a patient, from the more problematic possibility of editing individuals in ways that can be inherited.  The latter is what worries me.  I wrote about this last November 9 and November 16.   And yes, the current Chinese work should be more closely regulated.  Doubt we have any control over that.

An FDA blog post from a year ago (by the former FDA Commissioner) provides a useful, brief discussion of the FDA’s approach to regulating various applications of genetic editing.  Worth reading.

What’s really happening with doctor-assisted suicide?

Recently, Wesley Smith posted on the National Review’s “Corner” blog new concerns that Oregon’s “Death With Dignity” law may not be as tightly regulated as advertised.  Specifically, a Swedish fellow named Fabian Stahle, who evidently is troubled by the prospect that his country might embrace doctor-assisted suicide, claims to have carried out an e-mail exchange with someone in the Oregon Health Authority to ask how the law is interpreted in that state.  The responses included a statement that, to qualify for assisted suicide, a patient must have a “terminal illness” but said illness could include a potentially treatable condition which, if allowed to take its course without treatment, would be expected to cause death within 6 months.  That suggests that assisted suicide might be legally employed in Oregon in cases in which the patient refused treatment or the patient’s insurance company refused to pay for effective treatment.  The Oregon official cited by Mr. Stahle is quoted by him as having written that “the law is best seen as a permissive law…[that] does not compel patients to have exhausted all treatment options first, or to continue current treatment.”

You can read Mr. Stahle’s entire account here.

I must say that, while I mention this for this blog, I have not attempted to confirm these assertions by contacting the Oregon officials myself, and my first reaction is skepticism that what Mr. Stahle reports is in fact the correct interpretation of the Oregon law.  Even I, a staunch opponent of assisted suicide, must allow that the intent of such laws seems to be that assisted suicide is intended for cases for which potentially effective treatment options HAVE been exhausted.  But I suppose that further investigation is in order.

While at it, Wesley Smith also cited a 2005 British House of Lords inquiry into the Oregon law, from which a group apparently opposed to assisted suicide posted some comments here.  The entire House of Lords transcript, BTW—all 744 pages of it!—is available here for interested parties.  I must confess I have not had time to read the whole thing.

The most recent data summary from the state of Oregon that I am aware of is for 2016.  It reports 133 deaths from taking drugs from 204 lethal prescriptions filled in the state in 2016.  These numbers were slightly down from 135 and 214 in 2015.  The 2016 “death with dignity” rate is cited as 37.2 per 10,000 deaths in Oregon.  Of the 133 people who died with medical assistance in Oregon in 2016, 96% were white, about 80% had cancer, nearly all had some form of insurance, and about 85% were age 65 or older.  The two most commonly-stated reasons for seeking assisted suicide were loss of autonomy and loss of enjoyment of life—about 90% in each case.  Inadequate pain control was listed for about one-third of the cases.  The median time the patient had been seeing his or her prescribing doctor was 18 weeks, and the prescribing doctor was present for 13 of the 133 deaths.

Of course, all of this assumes the reporting is complete and accurate.  I have no information that would lead me to believe otherwise.  I state the facts in the preceding paragraph without commentary or, in some cases, without the irony I feel in reading them.

I can’t conclude from the Oregon report that patients who availed themselves of assisted suicide there were foregoing potentially effective treatment for their disease, much less that an insurance company refused to pay for it.  Of course, there is the one famous case of a person there getting a “suggestive” note about PAS from his insurer, some years ago—I can’t locate it at the moment.

In general, I’d say that the concerns raised through the above-mentioned posts are ones we must keep in mind, but that the slope may not yet have gotten that slippery.

Finally: the National Academies of Science, Engineering, and Medicine will hold a conference in Washington DC on Monday and Tuesday, February 12 and 13.  Looks like a webcast is available.  You can find information about it, and sign up to attend in person or by the web, here.  I’m going to try to at least watch some of it. From the information at that site:

This workshop will include discussions, and background materials, that address:

  • What is known empirically about the access to and practice of physician-assisted death in the U.S. and in other countries?
  • What are potential approaches for physicians, including those practicing in states where it is legal, those who receive a request for access when the practice is legal in nearby states but not in the state of practice, and those who practice in a state where it is legal but are personally opposed to physician-assisted death.
  • What is known about how palliative care and hospice services have incorporated the practice of physician-assisted death in states where it is legal?

“Nervy” SHEEFs, pain, and moral status

In May of this year, my brief essays (literally, “attempts”) on synthetic human entities with embryo-like features, or SHEEFs for short, sought to ask what sort of human cellular constructs might or might not enjoy full human moral status; to wit, the right to life.  Some experimenters with SHEEFs have suggested that, since they may bypass the early (14 days of life) markers that normal, or (if you will) canonical, human embryos demonstrate, a different moral approach is needed to determine ethical boundaries for these experiments, and the suggestion was that the capacity to feel pain would be a good substitute.

In my May 11 post, I suggested that a SHEEF with even part of a human nervous system must be accorded the right to life.  I made what is, I confess, a breezy connection between said nervous system, however rudimentary, and the identification of a human soul, on the grounds that bodily expression of human capacities commonly is through the effects of the nervous system.  The capability of any such capacities, I wanted to hold, would mark a SHEEF as a “human being” deserving of moral status.  This would distinguish it from, for example, a tissue-engineered trachea, or a kidney, or maybe even a heart, although human heart have, in their automatic conduction systems, a sort of “nervous system” capacity, I suppose.  Still, it didn’t seem to me (Edgar Allan Poe notwithstanding?) that a tissue-engineered heart would be considered a “human being,” the sort of being with “the intrinsic capacity to develop sentience, to ponder the universe, to comprehend the inevitability of mortality, to seek purpose, to yearn for love, and to suffer?”

That last quoted phrase is from a welcome essay by Dr. William Cheshire in the Fall 2017 edition of the journal Ethics & Medicine.  In his essay, “The moral significance of pain for synthetic human entities derived from embryo-like cells,” he argues, to put it all too briefly, that the ability, the realized capacity, to feel pain is an inadequate marker of human moral status.  Why?  Because some humans are incapable of nociception—physical responses to noxious stimuli.  Indeed, local anesthetic makes an otherwise fully-thriving human numb, for a while.  To say that all SHEEF experiments are OK as long as the entity doesn’t feel pain is to reduce meaning to pain, pleasure, and happiness.  Dr. Cheshire muses about a hypothetical creature, designed and bred in the laboratory, that is “sentient…possessing a complete brain composed of human neurons, yet lacking critical genes necessary for the capacity to experience pain…Rather than ask, what does it mean for a human organism to experience pain, a better question is, what does it mean to be the kind of being that experiences pain?  What does it mean to be the kind of being who has “the intrinsic capacity to develop sentience,” etc?

I was surprised when I saw that Dr. Cheshire chose for an epigram to his essay this sentence from my May 11 post:  “A moral boundary is approached when a human nervous system is brought into the plan.”  I read his essay as a criticism of my approach, but I still think the latter has merit.  I still think that some human tissue engineering with some SHEEFs might be ethical.  At the same time, I think that attempts to make too complete, too complex a SHEEF—for example, one with a whole human body except the head—would be monstrous.  I suppose that such a being would have to have a fair amount of human autonomic nervous system to function at all, and so would fall under my criterion.  And I also think that a quest for a “minimal human genome” or a “minimal human” would be frankly unethical.  (I understand synthetic biologists to be interested in the former but nobody to be suggesting the latter.)  To be ethical, experiments would have to observe serious limits from the concept stage.  And a concept of “how far can we go before we truly have the kind of being with the intrinsic capacity…?” would be out of bounds.

Check out this June 15, 2017 cartoon from the New Yorker

More about gene therapy and human gene editing

To my post of last week, add the case of a 44 year-old man who has received gene therapy for an inherited metabolic disease called Hunter’s syndrome. This is another example of a form of gene editing as true therapy.  That is, an existing individual is given a construct intended to edit his genes to introduce a gene that makes an enzyme that is lacking in the disease, and that causes terrible problems.  In this case, as part of a clinical trial, the construct, using a so-called “zinc finger” technique, is intended to introduce the gene into only about 1% of the patient’s liver cells.   If successful, the damage already done by the disease won’t be affected, but it’s progress may be arrested, with the potential to avoid having to have repeated, costly treatment with the missing enzyme protein itself.

Cool idea–and well within the current regulatory ethical regime.  The edit would not be inherited, and unborn humans don’t have to be sacrificed to develop the technique.  The adult patients are capable of giving informed consent.  Trials in children would come later, controlled by accepted ethical experimentation on children in clinical trials.

In a separate note, on a separate topic, Nature Biotechnology is editorializing that inherited gene editing is way behind mitochondrial replacement therapy (MRT), the “3-parent baby” approach to treating genetic problems, and will likely have limited use in the future.  Why?  Because it is likely that preimplantation genetic diagnosis (PGD) after in vitro fertilization (IVF) will be preferred to identify and give birth to babies unaffected by serious genetic disorders.  The journal editors argue that gene editing would be preferred only in those few cases where PGD cannot avoid passing on a disease–for example, in cases where it is known that all embryos from a fertilizing couple would be affected. Otherwise, the gene editing would not be worth the trouble.

MRT, on the other hand, has been studied more and is closer to being used to treat unborn humans who have diseases that MRT could treat.  Thing is, those diseases are also rare, on the order of 1000 cases per year in the US, and technically, gene editing would probably not be too useful for those.

There is a lot of talk about using a mix of gene editing and PGD to eliminate certain genetic disease from the human prospect.  I recently wrote about the Chinese government working on this.  To achieve the goal absolutely, every born human would have to be a product of IVF.

And the risk of some of the disorders is low enough that the absolute risk in any one “natural” pregnancy would be low.  So why go to the trouble of trying to eliminate the risks utterly?  (I think that’s a rhetorical question.)

The title of the editorial in question is “Humans 2.0.”  Indeed.

There’s gene therapy and there’s gene therapy

I’ve seen a number of different things described in the general press as “gene therapy.” But they are indeed different.  It’s important to be specific.

For one, there’s the situation where a set of mature human cells are obtained from the person to be treated and genetically altered outside the body to make them into a potentially useful treatment, then re-administered (by vein) to the patient.  Such is the case with so-called “CAR-T” therapy, which is well handled by current regulatory structures.  Main ethical issues: common human subject research concerns, regulation of the quality of the cells, and whether the treatment, which can be dramatically effective, is worth the high price.

Then there are situations where a diseased tissue is altered to make it normal, like the recent report of how a mutation in the skin of a boy was altered, and the repaired skin grafted back on, to spread over most of his body and replace the defective skin.  Again, way cool, well dealt with by current ethical and regulatory structures.

Or, similarly, Spark Therapeutics’ LUXTERNA, which is a gene injected into the eye to repair a defective gene causing blindness, literally restoring some sight, recently recommended for approval by an advisory committee to FDA.   Truly a gene made into a therapy.

Where the ethical issues get thorny is when one speaks of possibly editing a gene in a person–likely an unborn person very early in development; i.e., and embryo–in a way that can be inherited over generations.  I and others have discussed this recently on this blog.  See for example my post of last month (October 5).  Adherents say that there are serious diseases demanding cures, and that those who would counsel caution are obstructionists who fret too much about enhanced Olympic athletes.  (Example here, but subscription required.)  But the ethical issues are several: How safe and reliable will the technique be, and how much testing should be required before trying to birth “edited” babies?  How many embryos will have to be destroyed to perfect the approach?  How can we know whether there will be unforeseen long-term effects, after several generations?  How much should we care about that?  How will discrimination be avoided?  What are the implications for control of human reproduction–no more babies from sex? And who will decide and control that?

And–where, short of the Olympics, will it all end?  Should we try to edit genes that are known to increase cancer risk, to eliminate them from the human race?

The Hastings Center recently convened journalists to discuss some of the ethical issues with gene editing.  But even then, they are more concerned about whether there is a parental duty to “edit” the next generation.  Precautionary deliberations appeared to be limited to environmental concerns from the use of “gene drive” to spread genetic modifications rapidly through entire plant or animal species.  (Fair enough, but I’d extend the precautions to humans, where “gene drive” is not an issue.)  And, helpfully, the Hastings symposium did ask, will general press coverage necessarily be biased because reporters’ sources are the very scientists who tend to be enthusiasts?  In any event, the Center should not only do more public education events, but should make much more of the detailed content from such symposia available to the public for free, online, much as the Presidential bioethics commissions do.  As it is, we are left with their brief press releases, usually.  Thin gruel, IMHO.

Regarding objections to the change in the contraceptive coverage rule

The Journal of the American Medical Association carries a “Viewpoint” piece that categorically rejects the Trump administration’s reversal of its predecessor’s mandate that employer-based health insurance include payments for contraceptives.  As reported in the general press, the current administration’s new stance was hailed by religious and other political conservatives as a welcome support of conscience rights.

Read the article here.  Briefly, some key points and quick responses:

  1. “The Trump administration has rejected balance [between conscience rights and access to contraceptives] as a worthwhile goal.”  The prior rule was widely understood to be narrow, intending to apply only to religious organizations and not to private employers who held sincere and consistent objections to some or all forms of contraception.
  2. It is argued that religious freedom should not be privileged over “women’s rights” or “the interests of patients.”  However, religious freedom is arguably protected, explicitly, in the US Constitution.
  3. “Ethical obligations to prioritize the interests of patients” are wrongly compromised.  This claim seems to wrongly invoke the obligation of a physician to prioritize the patient’s interest over his own.  This is not the same as claiming that a woman’s right to seek and obtain contraception entails an obligation by anyone and everyone to provide it for free.
  4. “Government should intervene” to ensure all women have access to free contraceptives.  Even if the cost of some contraceptives is prohibitive to some women of limited means, that does not entail the government creating an obligation for private citizens or groups to violate their strong moral convictions by direct or close involvement in providing said contraceptives.  The government could pass legislation and appropriate funds to provide the contraceptives more directly, eliminating employers as middlemen.
  5. The order is claimed to prioritize conscientious objections over “evidence,” in this case evidence that contraceptives are not abortifacients.  This claim, which cites a blog post as evidence and is not further developed, seems to rely on a definition of abortion as occurring only after implantation.  I don’t believe that it has been conclusively proven that at least some contraceptives cannot work after fertilization.