The Clinical Utility of Surrogate End Points Sparks Debate in Oncology

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The virtual revolution over the past several decades in our understanding of the basic molecular biology of malignancy has resulted in a substantial increase in novel antineoplastic agents for the treatment of patients in numerous clinical settings. The FDA has responded to this development by permitting nontraditional study designs and what is labeled accelerated approval as relevant components in its regulatory paradigm. One critical component of this process has been the use of so-called surrogate end points, which, in FDA parlance, means study outcomes likely to predict clinical benefit, assuming that the surrogate end point itself is not directly meaningful to patients for some reason. One can appropriately debate the value of achieving a prospectively defined and objectively measured clinical end point.

However, the specific issue to be highlighted here is that use of such surrogates may substantially decrease the time required for a novel antineoplastic agent to be approved for noninvestigative commercial sale. This is compared with the standard process in which it is mandated that the agent achieve success by demonstrating statistically significant improvement in the declared gold standard of overall survival (OS) in a phase 3 randomized trial.

Unfortunately, some experts—mostly from the realm of academic medicine or individuals with little direct knowledge or experience with clinical cancer medicine—have raised strenuous objections to the use of surrogate end points for full regulatory approval, including an improvement in progression-free survival (PFS), an objective primary study end point increasingly employed in the FDA’s decision-making process.1

The commentary focuses on the reason why PFS is often likely to be the most appropriate primary study end point, recognizing that, unquestionably, patients and their families ultimately desire to improve survival, not simply the time until the cancer progresses.

Looking Beyond the Trial

The major issue is the fundamental question of what happens to individuals on the study after they have completed therapy on a clinical trial? Specifically, how might a comparison in OS between experimental and control management arms in a regulatory-defined phase 3 randomized trial be influenced by subsequent therapy in the study patients?

In an era where there are limited or no known beneficial “next-line” treatment options available for patients completing study-based therapy, or at least options that have any realistic opportunity to measurably influence survival (eg, objective response rates of < 10%, with durations of approximately 1 to 3 months in individuals achieving a response), it is reasonable to anticipate that a statistically significant improvement in PFS in a randomized phase 3 trial should be able to be translated into an improvement in OS. In fact, in this specific scenario, it would be rational to suggest PFS would be serving as a surrogate end point for a subsequently observed improvement in OS from the time of initiation of therapy on the clinical trial.

However, in a clinical setting where there are a number of possible therapeutic options available that may favorably affect the subsequent survival of patients (who were previously research subjects) including surgery, radiation therapy, commercially available antineoplastic agents, or promising investigative drugs, it is difficult or objectively impossible to know how such therapy may influence the ultimate measure of the OS of the study population. Unique clinical features may help determine next-lines of treatment available to patients previously treated on study, such as surgical removal of a progressing solidary lung or abdominal cavity mass; localized radiation for a progressing isolated pelvic wall mass; or anti-cancer treatment with multiple possible agents revealed in published results of phase 2 trials to have a meaningful degree of clinical activity in this setting.

Surrogacy 101: Everything you need to know about having a baby with a surrogate

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About one in eight couples in the U.S. struggle with infertility,and many consider alternate methods of having a baby. Priyanka Chopra and Nick Jonas announced on January 21 that they welcomed their first baby via a surrogate.

Back in April 2021, NBC News’ Kristen Welker and her husband, John Hughes, announced on TODAY that they are expecting their first child with the help of a surrogate. Margot Lane Welker Hughes was born on June 12.

Surrogacy is a wonderful option for people who want to become parents. But the surrogate pregnancy process is still surrounded by mystery and confusion.

To help understand how it works, TODAY Parents paged Dr. Barry Witt, a reproductive endocrinologist, OBGYN and Medical Director with WINFertility.

What is surrogacy?

Surrogacy is an arrangement between two parties, where a woman, the surrogate, agrees to carry a pregnancy for the child’s intended parents or parent. There are two different types of surrogacy: gestational and traditional.

Gestational surrogacy uses the egg of the mother and the sperm of the father or sperm donor to create an embryo, which is then transferred to the uterus of the surrogate via in vitro fertilization.

In traditional surrogacy, the surrogate’s own egg is used, making her the biological mother of the child. Sperm is implanted into the surrogate’s uterus through intrauterine insemination (IUI.)

Witt doesn’t recommend traditional surrogacy.

“The traditional method is rarely done because it’s legally and emotionally complex,” Witt explained. “In cases where someone needs a donor egg, they’ll use a donor egg and have that transferred into a gestational surrogate. That separates whose egg it is from the person who’s carrying the pregnancy.”

Why choose surrogacy?

There are a wide variety of reasons that a couple may decide to hire a surrogate.

“One of the most common would be that the woman has problems with her uterus or she doesn’t have a uterus," Witt said. “Surrogacy is also a good option for a woman with medical problems like cancer, severe heart disease or pulmonary hypertension.”

Same-sex couples who want to be genetically connected to their child are also drawn to surrogacy. Neil Patrick Harris and his husband, David Burtka, welcomed their twins with help from a surrogate in 2010.

How do you find a surrogate?

“Most people turn to agencies,” Witt said. “But some will ask someone they know like a sister. The advantage of doing that is that you can save a lot of money. Carriers get paid roughly $30,000 to carry a pregnancy.”

But there are also benefits to using agencies, which have a rigorous screening process to ensure that the surrogate is emotionally and physically prepared for the journey.

How do you become a surrogate?

The American Society for Reproductive Medicine (ASRM) recommends that the surrogate should be between the ages of 21 to 45 and should have carried at least one healthy pregnancy without complications. Ideally, she should have had no more than five prior pregnancies and no more than three C-sections. The ASRM also notes that many reproductive endocrinologists maintain that a carrier should have a body mass index of less than 30.

How many babies are born through surrogacy each year?

The number is roughly 3,000 to 4,000, according to Witt.

How much does surrogacy cost?

“It’s a very expensive process — I believe it costs people about $150,000 in total,” Witt noted.

Increasingly, employers are offering financial aid for couples struggling with infertility and for those who want to pursue surrogacy. Some surrogacy agencies also offer assistance through grants and loans.

Do you need a surrogacy attorney?

In surrogacy, it’s crucial to have all legal paperwork in place, according to Jeffrey A. Kasky, a Florida surrogacy lawyer. It’s definitely not the place to try to cut your expenses.

“That is what is going to determine who the actual legal parents are,” Kasky told TODAY Parents. “Here’s a child that’s being created through alternative means that was not contemplated by common law. And in order to secure your rights, you need a legal contract.”

When speaking with TODAY in 2019, Kasky stressed the importance of hiring a knowledgeable attorney.

“Like adoption, surrogacy is a specialized area within family law which requires a specific type of experience,” Kasky said. “When push comes to shove, there are eventualities in which the legal work can be what saves you from disaster and heartbreak. You don’t want to trust that responsibility to just anyone.”

Here are more resources:

Surrogacy Agencies:

Choices Donations

Creating Families

Pacific Egg Donors

Growing Generations: Full service surrogacy agency offering grants of up to $50,000 for qualified intended parents

Books:

Children’s book about surrogacy: “You Began As a Wish”

Book for adults about assisted reproduction: “Your Future Family: The Essential Guide to Assisted Reproduction (What You Need to Know About Surrogacy, Egg Donation, and Sperm Donation”

Organizations:

American Society for Reproductive Medicine: Resources for prospective parents going through fertility care

Family Equality: Resources for LGBTQ families, parents and parents-to-be

Resolve: Resources for anyone challenged in their family building process

Society for Assisted Reproductive Technology: Organization for assisted reproductive technology professionals

Men Having Babies: Financial assistance and resources for gay men pursuing parenthood

‘I gave birth to my own grandson’: Mum, 54, becomes Australia’s oldest surrogate

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‘Australia’s oldest surrogate’ has given birth to her own grandson at 54 years old after carrying for her daughter who was born without a uterus

At 17, Meagan White, from Lilydale, Tasmania, was diagnosed with Mayer-Rokitansky-Küster-Hauser syndrome (MRKH), a disorder that meant she could never carry a child.

The now 28-year-old, who has a background in nursing, feared her dream becoming a mother would never come true after their baby girl, carried by a Canadian surrogate, sadly passed away at 21 weeks.

But after doing research, Meagan’s mum Maree Arnold discovered she could be a surrogate for her daughter - and gave birth to her own healthy grandchild Winston lon via C-section on January 13.

Australia’s oldest surrogate has given birth to her own grandson at 54 years old after carrying for her daughter who was born without a uterus

At 17, Meagan White (right), from Lilydale, Tasmania, was diagnosed with Mayer-Rokitansky-Küster-Hauser syndrome (MRKH), a disorder that meant she could never carry a child

The C-section was planned months ahead and the birth went entirely to plan; the group arrived at hospital at 7am and by 9am they had little Winston in their arms.

‘It was and is a dream come true. When we first saw him, it was love at first sight. He has filled out hearts in a way we never knew possible,’ Meagan said.

‘We were both present for the birth. Not nervous but just excited, our doctor was fantastic, informative, and calming.’

Maree, who is a mother-of-five and works on her own farm, said the birth was ‘perfect’ and she was thrilled to be able to carry her grandson.

The C-section was planned months ahead and the birth went entirely to plan; the group arrived at hospital at 7am and by 9am they had little Winston in their arms

‘I always just assumed I’d be too old to do something like this, but it just goes to show you always need to ask questions. It is such a special experience for me and I’m over the moon to be able to help my daughter,’ she said.

With Maree already having gone through menopause, she was given medications to reverse the process and thicken her uterus lining to prepare for pregnancy.

After three failed embryo transfers, Meagan and Maree said they both began to feel a bit defeated and thought perhaps the process was not going to work.

But thankfully, the fourth transfer was a success.

‘I know that I was obviously older with this pregnancy, and I did get a bit more tired than when I was last pregnant 22 years ago,’ Maree said.

‘But I was still up and about, mowing the lawns and doing this around the house. I felt great. Now that it’s all over I think I’m relieved it all went so well and just amazed at this little human we have made.

‘I know that I was obviously older with this pregnancy, and I did get a bit more tired than when I was last pregnant 22 years ago,’ Maree said

‘My first cuddle was super special and one I will never forget.’

Maree said little Winston is everything they could ask for and more and loves seeing Meagan and her husband Clyde so happy.

‘I just hope our story will encourage someone else to take the same journey as we did - I would definitely do it all again.’

Meagan knew something was not quite right years ago when all the girls at school had started their periods, except her.

‘Mum and I went to see a doctor and discovered I had MRKH, which means I was born without a uterus and therefore would never have a period,’ she said.

‘I just hope our story will encourage someone else to take the same journey as we did - I would definitely do it all again,’ Maree said

‘It also meant I could never carry a child; however I did have working ovaries so I could have a biological child with the help of a surrogate.

‘Of course, as I was just a teenager at the time, I didn’t think about it much. But after meeting my now-husband Clayde, 28, in 2015, I knew I wanted to start a family and be a mother.’

The pair looked into surrogacy and found a volunteer overseas in Canada through an agency named Allison in January 2019.

‘We got to know her virtually for nine months, before flying over there in September 2019 to meet her in person. Shortly after returning home to Australia, we went ahead with the first transfer which failed, but the second was successful and Allison got pregnant in December 2019,’ Meagan said.

Mum and daughter both agreed that this experience has made them closer than ever

‘In March 2020 doctors told us our baby girl had not developed kidneys and would not be viable with life.

‘Everyone was heartbroken, and after that I just felt like giving up. Then once the pandemic began, overseas travel was prohibited, so everything felt impossible.’

Maree said she was heartbroken watching her daughter suffer but never imagined she could volunteer to be a surrogate, as she believed she would be deemed ’too old’ to be allowed to carry a child - thankfully that wasn’t the case.

Maree could possibly be Australia’s oldest surrogate to date, with Antonietta Di Maggio, from Sydney, making headlines back in 2015 for giving birth to her grandson for daughter Claudia Luca at the age of 53.

Mum and daughter both agreed that this experience has made them closer than ever.

‘Mum and I are so close; we talk every day. I can’t even put it into words how grateful I am for her,’ Meagan said.

‘Our relationship is so special. There is nobody else I’d rather have gone through this with.’

From surrogacy to free speech: do you know your legal rights?

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If my neighbour’s cat eats the fish in my pond, is the owner liable?

“It all depends on what you mean by ‘cat’. Section 2(1) of the 1971 Animals Act imposes strict liability on the keeper for damage caused by an animal that belongs to a dangerous species (a tiger, for example). Section 2(2) of the Animals Act imposes strict liability on the keeper for damage caused by an animal that does not belong to a dangerous species (a domestic cat, for example), only if the damage was of a kind that was likely to be severe and the likelihood of the damage was due to abnormal characteristics not normally found in animals of the same species and those characteristics were known to the keeper.

There is nothing abnormal in a domestic cat killing and eating fish. Although an action in negligence might be contemplated, even if the owners owe a duty of care to their neighbours in these circumstances (and that is doubtful), there are no specific precautions that a reasonable cat owner could be expected to take in order to avoid the unfortunate occurrence in question. Pond owners should consider buying netting or a pond cover, using sprinklers or a water gun, or providing shelter for their fish in a pond that is at least 2ft deep.

Paul Eden, senior lecturer in law

If I use a surrogate in the UK and they change their mind after giving birth – even if the baby isn’t genetically theirs – who is the legal parent?

The surrogate will always be the child’s legal mother, regardless of the method of surrogacy or whether they are the biological mother or not. This is the case whether the surrogate was in the UK at the time of the insemination or whether they were abroad. English law doesn’t allow a surrogate to give up their legal parenthood before the making of an order by a judge after a court process. There are no pre-birth orders in England that terminate the surrogate’s legal rights as there are, for example, in California. Even if a pre-birth order has been made in respect to a child born abroad and the surrogate is not considered to be a legal parent in the jurisdiction of birth, the law in England will treat them as the legal mother until a court order is made terminating their parenthood.

If the surrogate is married or in a civil partnership at the time of conception, her spouse/civil partner will be the child’s second legal parent; unless it can be shown that the spouse/civil partner did not consent to the surrogacy arrangement. As with the surrogate mother, legal parenthood will only be terminated on the making of a court order.

The question of what happens if a surrogate changes her mind is probably the first question on the minds of any intended parents. Firstly, it is important to say that this situation is very rare, but it does happen and the child’s intended parent(s) may not be his/her legal parent(s) when the child is born. In this situation, it would be imperative that the intended parent(s) take the necessary steps to secure their legal position. Decisions about the care arrangements for the child will then have to be determined by the court.

Hilda O’Justus, assistant solicitor and Jemma Dally, partner at Goodman Ray

If you are naked in front of a window in your own home, is that considered indecent exposure?

Under section 66 of the Sexual Offences Act 2003 an offence of indecent exposure can be made out if a person intentionally exposes their genitals with the intention that a person in a public place (such as outside a window) sees them and is alarmed or distressed by that behaviour. Indecent exposure is a crime of specific intent. Therefore, if it can be proved that your intention was not to expose yourself or to be seen, you have an absolute defence.”

Myles Jackman, obscenity lawyer

When is a signature legally passable?

The handwritten signature has been in decline for many years and this fact became more apparent when the Law Commission ruled in 2018 that electronic signatures are, in most cases, a viable alternative to handwritten ones. Recent case law has confirmed that, regardless of the type of signature, if the person’s intention was to authenticate the document, then the signature will be valid.

For instance, when we accept a parcel, the scrawl we use on the delivery driver’s screen rarely bears a strong resemblance to our physical signature. Legal documents that previously required manual signatures – such as property sales, credit agreements and the granting of power of attorney – can all now be done with the click of a button.

That said, when it comes to signing cheques, the back of credit cards, driving licences and passports, we’re still following the old practice of using pen and ink. For these types of documents, there legally has to be a strong resemblance to the original, which would have been kept on file.

Daniel Wise, associate solicitor at Slater Heelis

If you are caught speeding to a hospital in an emergency, is it still illegal?

Speeding to the hospital is illegal and is not a defence in law. However, special reasons can be put forward to avoid a penalty. This means that the circumstances outlined give the court the discretion to not endorse a licence with points or disqualify someone from driving despite the offence being admitted. In fact, these special reasons can actually be applied to all driving offences. If you are pulled over by the police on an emergency dash to hospital that is clearly obvious, a sensible approach is usually taken. It has been known for police to give a blue light escort for women in labour, too.

Hannah Costley, solicitor at Slater Heelis

Do I have any inalienable rights or could a sitting government remove them – for example, free speech – in the UK?

Freedom of expression under Article 10 of the Human Rights Act is not an absolute right (encouraging racial or religious hatred is expressly prohibited). The state may also restrict an individual’s right to free expression if it can demonstrate its action is lawful, necessary and proportionate in achieving one of the following aims: to protect national security, territorial integrity, or public safety; prevent disorder or crime; protect health or morals; protect the rights and reputations of other people; prevent the disclosure of information received in confidence; or maintain the authority and impartiality of judges.

Myles Jackman, obscenity lawyer

If you borrow something without the owner’s knowledge with the intention of returning it, is it still considered theft?

Theft is defined in section 1 of the 1968 Theft Act as dishonestly appropriating property belonging to another with the intention of permanently depriving the other of it. Borrowing something without the owner’s knowledge with the intention of returning it would not satisfy the definition of theft as the intention of permanently depriving the owner of it would be lacking.

If someone takes cash without the owner’s consent intending to repay it, the fact that they intend to repay it may negate the dishonesty aspect of theft, but it will not negate the intention to permanently deprive, unless they intended to return the exact same notes or coins to their owner.

Paul Eden, senior lecturer in law

If I push someone out of the way of a moving car and break their leg in the process, am I liable?

This is not an easy question to answer, but there are two points that can be made. First, if your intervention causes the victim to suffer less harm than they would have done if you had not acted at all, then you should not be found liable. It may be possible to argue that the manner of your intervention was negligent and that a reasonable person would have intervened in a manner that did not cause any injury at all (or less injury than occurred), but the courts have taken the view that a volunteer’s only duty is not to make matters worse than they would have been if they had done nothing.

If, however, your actions caused more harm than would have resulted if you had not acted at all (you were mistaken in your belief that the car posed a threat, for example), then it is probable that you will be found liable.

Paul Eden, senior lecturer in law

If you administer first aid and do some sort of damage in the process, are you liable?

The law looks differently at a nominated first aider and an innocent bystander who intervenes to help. Generally, a trained first aider would be expected to demonstrate a higher level of knowledge and expertise than a random person on the street who steps in to help. If the first aider can prove that they took reasonable care, they are unlikely to be found to have breached their duty of care to the ill or injured person.

For the bystander, there may be a strong instinct to intervene and help, but the law will still judge the level of care provided. If there is a failure to take reasonable care, such as breaking a rib when giving the Heimlich manoeuvre, then you could be liable for that injury. By starting treatment you are accepting a responsibility for the wellbeing of the person you are treating. Put simply, it is not considered sufficient for a well-meaning person to do their incompetent best.

Richard Wilson, partner and personal injury solicitor at Slater Heelis

Who legally owns a pet? If a couple gets one together, who has custody if they split?

Although a pet for many couples feels like part of the family akin to a child, on separation a pet is not treated in the same way as a child. It is very common when relationships break down for there to be disagreements and arguments over who gets to keep the family pet.

A pet is treated by the courts like an item of personal property, such as a piece of furniture, jewellery or artwork. When deciding who gets to keep the pet it can come down to who bought it – for example, whose money was used to buy the pet and consideration might be given to who has financially paid for the pet during its lifetime. Very little weight would be attached to who has cared for the pet in terms of future ownership.

The best advice is not to get hung up on this matter and end up spending significant funds in legal fees arguing over the family pet. It’s better to try to reach an agreement with your ex-spouse or ex-partner and agree perhaps on a shared custody arrangement so the pet spends some time with both of its previous owners.

Trudi Featherstone, partner and mediator at Goodman Ray

If my neighbour’s tree overhangs into my garden, do they have a responsibility to cut it back?

The boundary line is the deciding factor in this issue – if branches or roots cross the boundary of your property, you are entitled to cut them back, but at your own cost.

Under common law, a neighbour can’t be compelled to carry out this work, but in the spirit of amicable relations, we would advise a friendly discussion before taking any steps. Trees protected by tree preservation orders and land in conservation areas require a much closer look at the law before any work is undertaken. We would advise getting professional advice in these cases.

Zara Banday, partner and head of the residential property team at Slater Heelis

Find out how The University of Law could open the door to a whole range of exciting careers

Oireachtas committee given three months to make surrogacy recommendations

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A special joint Oireachtas committee is being set up to examine the issues around surrogacy.

Amid ongoing discussions over the matter, Justice Minister Helen McEntee, Health Minister Stephen Donnelly, and Minister for Children, Equality, Disability, Integrity and Youth, Roderic O’Gorman, confirmed that they had been given Government approval to establish the committee.

The committee will give consideration to the rights, welfare, and interests of children born through surrogacy.

Current law

At present, there is no regulation of surrogacy - either altruistic or commercial - in Ireland, meaning most surrogacies undertaken by Irish people are commercial arrangements undertaken outside the State.

The law states that the biological or genetic father of a child born through surrogacy may apply for a declaration of parentage in respect of the child under Section 35 of the Status of Children Act 1987.

If the declaration of parentage is granted, the father may then apply for guardianship.

The current law also states that the intending mother of a child born through surrogacy, not being the birth mother of the child, is not entitled to apply for a declaration of parentage under the 1987 Act, even if she provided the egg used in the surrogacy arrangement and is therefore the genetic mother of the child.

Instead, she must apply under Section 6C of the 1964 Act to be appointed the child’s guardian if she is married to, or in a civil partnership with the child’s parent, or has cohabitated with the child’s parent for more than three years and had shared responsibility for the child’s day-to-day care for more than two years.

Minister for Justice, Helen McEntee: “I know how important this issue is for many families in Ireland.” Picture: Leah Farrell / RollingNews.ie

New legislation around assisted human reproduction is now being drafted by the Department of Health and Office of the Attorney General.

The Health (Assisted Human Reproduction) Bill will make provision for assisted human reproduction and associated areas of research, and will set out specific provisions under which surrogacy will be permitted in Ireland.

However, several groups, including Irish Families Through Surrogacy, have raised concerns that the bill in its current form would leave families who availed of international surrogacy without legal protection, given it does not contain provisions to regulate surrogacy arrangements undertaken in other jurisdictions.

Timeframe

The new Oireachtas Committee will report with recommendations within three months of its establishment, though there is the possibility that this timeframe could be extended.

Thereafter, any new necessary legislative proposals will be submitted to Government.

Speaking this morning, Ms McEntee said the cross-party committee was “best placed to examine all of the complex issues surrounding international surrogacy and to make recommendations based on the analysis of that evidence.”

“I know how important this issue is for many families in Ireland. Recognising this, the timeframe in which we are asking the Committee to complete its work is ambitious,” she said.

Health Minister Stephen Donnelly said the Government and his department were “committed to legislating for surrogacy in Ireland” and that the establishment of the committee would be an important step in “recognising and supporting the variety of different family units we have here.”