ETHICAL, LEGAL AND SOCIAL ISSUES IN DRUGDEVELOPMENT AND PHARMACOGENOMICS:Report on a Qualitative Study of the Perspectivesof Canadian StakeholdersSHANNON GIBSONUniversity of TorontoFaculty of Law
Presentation OverviewIntroduction• Study Methods and ObjectivesAreas of Ethical, Legal and Social Concern• Regulating in the Pharmacogenomics Context• The Drive Towards Niche Markets• Fairness of Study Design• Cost Implications of Niche MarketsIntroduction
Objectives• Capture perspectives of key informants on different aspects of pharmacogenomicdrug development, particularly the ethical, legal and social issues involved.• Understand how different stakeholders view the opportunities and challenges ofpharmacogenomics to provide insight into the regulatory and policy responses thatare necessary to achieve the successful—and hopefully sustainable—integration ofpharmacogenomic therapies into the health care system.MethodsA total of 34 semi-structured interviews with key Canadian stakeholders,including:• drug regulators,• drug funders,• health technology assessors,• clinical researchers,• patent experts,• drug policy experts,• pharmaceutical industry representatives (brand and generic) and• patient advocates.Introduction
What is Pharmacogenomics?Pharmacogenomics: the study of the influence of genetic factors on drug response.• Depending on each individual’s genetic makeup:• Some drugs may work more or less effectively.• Some drugs may produce more or fewer side effects.Drug companies are developing an interest in increasing the efficacy of products bydeveloping companion diagnostic tests.• Ideally, the "one size fits all" model will give way to more “personalized”approaches where the "best-fit" drug can be identified at the outset.Regulating in the Pharmacogenomic Context“Until we have a much better picture – comprehensive perspective –on the genome instead of just these little snapshots, I really dislikethe thought of overpromising to the public that genomics can reallyhelp them make meaningful decisions in their life, about theirhealth. It’s disingenuous at best, it’s dangerous at worst.”- Policy Expert
Coordinating the Review of Drug and Test Components• For most pharmacogenomic therapies, the companion diagnostic is an essentialcomponent in ensuring the safe and effective use of the drug product.• Health technology assessment procedures should take a holistic approach inassessing pharmacogenomic therapies and consider both the diagnostic test andpharmaceutical product in tandem to ensure the combination of the drug andcompanion diagnostic is effective.Reviewing drugs and tests in tandem may help to establish their interdependenceand increase the likelihood that both will be made available and funded together.Regulating in the Pharmacogenomic Context“[Drug funders] should be assessing the evidencebehind the effectiveness and specificity and sensitivityof the test and how that relates to the treatment andthen the effectiveness and cost-effectiveness of thetreatment given the diagnostic test. At the momentthat’s not clear that that’s being done.”- Health technology assessor
The Drive Towards Niche MarketsChallenges of Modern Drug Development• In recent years, the pharmaceutical industry’s research and development costshave been increasing steadily, while the number of new drug approvals has beendeclining.• Many commentators predict the death of the blockbuster model of drugdevelopment.• As more and more blockbuster drugs come off patent, industry is increasinglyturning towards other areas of drug development, including pharmacogenomics,as a source of new drug discovery.“I would express a general concern thatcompanies would see an advantage indeveloping drugs that require identificationeither of a receptor, or in particular a metabolicstep, so that they could see an opportunity forthem to create a niche and co-market a test,…give some exclusivity, … have a patent on thetest as well as the product…”- Policy expert“The question is less about goingafter blockbuster drugs versus aniche product as it is [about]where are the markets—where isthe medical need.”– Pharmaceutical IndustryRepresentative
The Drive Towards Niche MarketsThe Equity Problem• There is a general concern in pharmaceutical development that drugcompanies, as for-profit ventures, are driven towards the mostprofitable markets—which often do not correspond with where thegreatest medical need exists.• Personalized medicine focuses on specific subpopulations, and therefore,it can increase the risk of health disparities.• Pharmacogenomics is sometimes viewed as a trade-off between lessexpensive drugs that work in a broad population, and much moreexpensive drugs that are effective for only a fraction of the population.“The question is: are we spending ourenergies and efforts on drugs that aregoing to be directed towards only a selectgroup of individuals and what does thatmean in terms of equity… and fairness.”- Policy expert“We felt it was in fact the responsibleapproach to actually figure out who is thebest patient for the medicine… it’sactually unethical to not do it.”- Pharmaceutical industry representative
Fairness of Study DesignEvidence Uncertainty in Niche Markets• As pharmacogenomic drugs are often narrowly targeted towards patients witha specific genetic marker, the population base on which to conduct clinicaltrials may be inherently limited.• Further, drugs for niche markets are sometimes fast-tracked during the drugapproval process, particularly where they treat life-threatening conditions orwhere no alternative treatment is currently available.Researchers sometimes “enrich” study populations to identify a population ofpatients in whom a drug effect, if present, is more likely to be demonstrated.• For pharmacogenomic drugs, diagnostic testing may be used to enrich thestudy population by selecting only biomarker-positive patients who are morelikely to respond to the drug—a strategy known as “predictive enrichment”.
Fairness of Study DesignFinding the Right Balance in Enrichment DesignWhile predictive enrichment may lead to smaller, more efficient clinical trialsthrough targeted patient selection, significant problems may arise if such studiesare not properly designed—particularly where the scientific basis for selectingpatients is unsound.• Biomarker groups who are unlikely to respond to a drug should likely be excludedif there are alternative treatments available. More importantly, if a genetic testcan accurately predict severe or likely adverse drug reactions, fair subjectselection may require excluding certain biomarker groups.• On the other hand, where the correlation between the biomarker and thetargeted therapy is weaker, excluding certain biomarker groups may beproblematic.“Patients should have all the power toassess their risk… Patients are the oneswho are taking all the risk—we’re the onestaking the drug into our body.”– Patient Advocate“A lack of evidence does not necessarilymean a lack of benefit... and weredealing here in a world where there isn’ta whole lot of evidence.”– Patient Advocate
Fairness of Study DesignPotential Responses Advantages DisadvantagesMulti-arm clinicaltrial: trial conductedin biomarker-positive,biomarker-negativeand control groups.• Ensures that drug is testedoutside of the biomarkergroup.• Helps to refine the linebetween responders and non-responders.• Trials may be more complexand time-consuming.• Potential ethical problem ofexposing biomarker-negativepatients to drug they areunlikely to respond to.Follow-up studiesthat test the drugoutside of the initialbiomarker group.• Allows the drug to beapproved faster for the initialbiomarker group throughtargeted clinical trials.• Only patients who are mostlikely to respond aresubjected to the drug.• May be significant delay inconducting the follow-upstudies.• Uncertainty over who shouldfund/conduct the follow-upstudy, or how regulators wouldenforce such a commitment.
Dynamics of Niche Markets• Where a disease is rare—and particularly where its life-threatening–and there arefew, if any, alternative treatments available, it becomes politically untenable fordrug funders to refuse to cover what may be the only treatment option availableto those with the condition, even if the drug is extremely expensive.• Moreover, there is little competition in niche markets, which means that there areusually no competing products to help drive down prices and the ability of drugfunders to negotiate for lower drug prices is thus compromised.Cost Implications of Niche Markets“The niche-busters seem to be working on the basisthat while it’s a small patient population, and industryis saying we can’t defray our costs across a largepopulation and therefore keep the prices down.They’re really using the political economy of rarity, ifyou like, to justify very significant payment.”- Health technology assessor“I don’t want to be cynical, butthe fact is that none of thetargeted therapies are cures…So companies make theirmoney over the long termversus short term. So the drugcompany has got a patient forlife.”- Scientist
The Issue of Cost• As the number of niche therapies entering the market continues to increase,there is growing concern over how long healthcare systems can sustain thispricing model.• Some new pharmacogenomic drugs may cost tens or even hundreds ofthousands of dollars for a course of treatment.• While many stakeholders understand the basic rationale for high prices inniche markets, there is also significant suspicion that industry may be gamingthe system in order to justify very high prices.Cost Implications of Niche Markets“If the industry is saying that the pricing isdependent upon the number ofbeneficiaries of the drug, or people youmight use it, and they start expanding thenumber of beneficiaries, presumablythere would be some price reduction—that follows from the logic that theindustry itself uses.”– Policy Expert (economist)“The signal that you send first bywhat you pay and how much youpay for it actually plays a wholefeedback loop to the industry asa signal to what we can developand where the money is.”- Regulator
Cost Implications of Niche MarketsImproving Coverage DecisionsFurther, uncertainty around the duration of treatment and the size of markets will likelymake funders reluctant to cover these often highly expensive drugs without somemechanism to control the potential cost implications.• Coverage with Evidence Development (CED): Healthcare decision-makers in variousjurisdictions are showing growing interest in CED, one of several terms used to describe“conditional” reimbursement models where funding for therapeutic interventions isprovided on a time-limited or conditional basis to allow for the collection of real-world dataaround its safety, efficacy and cost-effectiveness.More than anything, it’s generating theevidence. Evidence-based medicine justcan’t take hold until you have somereally good evidence to guide thedecisions.- Policy Expert“As patient advocates, we’re allin favour of programs withevidence development and werein favour of getting theinnovative drugs to marketfaster.”– Patient Advocate
Conclusion“There is always a concern about who’s notgetting treatment and who’s going to beexcluded. It’s a real concern that only thosepatients with a specific genetic mutation willhave access to any therapy. So it’s a bit of a crapshoot if you end up with the right type ofcancer—whether it’s one that’s currently underresearch for a genetic mutation or not.”– Patient Advocate