avoiding ESD damage with proper layout without esd protection devices

Can the likely hood for ESD damage be substantially or entirely eliminated with proper layout and enclosure with the absence of any esd protection devices?

Particularly for MOSFET zero volt switching a flyback transformer - are there any application notes or guides to safely implement this and other HV typologies without ESD protection devices?

Electrostatic discharge is a problem of inappropriate handling during production and discharge events hitting externally exposed circuit parts, not of internal generated high voltage.

A circuit should be designed so, that component maximum ratings aren't exceeded. There are some cases where a circuit generates overvoltage in special situations, e.g. overcurrent shutdown of a power switch. Protection devices like TVS diodes may be used to handle it.

ESD damage comes from a discharge into an exposed part of a circuit. There is little or nothing that can be done to mitigate this with layout alone. However, design of the enclosure can help.

I suppose ESD/TVS diodes are only useful if the circuit is enclosed from people touching the components and the voltage clamps should only be present were exterior connections/traces comes into the enclosed circuit.

Is this the case to mitigate damage from esd?

In order for ESD/TVS diodes (or transil diodes) to work correctly some rules have to be abode by. I had some bad luck with devices that were damaged from ESD discharge in spite of the fact they were protected with TVS diodes.
TVS diodes are not ideal devices. Although they are very fast but they have some inherent inductance. There is also some inductance in the leads and copper tracks on the PCB they are attached to. This inductance is very low, typically in 0,5..5 nH range. Such a value seems to be insignificant but it causes problems. One must keep in mind that ESD discharge current waveform has incredibly fast rising time - the current rises to about 35A in 1 ns. It's a real eye opener ! Before the clamping process in the TVS diode takes action there will be some delay caused by parasitic inductance (copper tracks and diode leads). This will produce substantial voltage on it - it can reach a few dozen volts that may easily destroy some components in your circuit. To fully protect the device against ESD additional resistors must be used in the path of the signal that is to be protected. For example, if the signal is to be fed into the input of A/D converter it is recommended to add a series resitor with a value of 100..500 Ohms. It will attenuate the current produced by the voltage that appears across TVS diode before it starts to clamp. It is also extremely important that TVS diode must be attached directly to the terminals of the connector where the signal comes in.